Method for treating inflammation

ABSTRACT

A method for treating IL-20 induced inflammation. An antagonist to IL-20 is administered to treat inflammation and associated diseases. The antagonist can be an antibody that binds to IL-20 or its receptor or a soluble receptor that binds to IL-20. Examples of such diseases are adult respiratory disease, psoriasis, eczema, contact dermatitis, atopic dermatitis, septic shock, multiple organ failure, inflammatory lung injury, bacterial pneumonia, inflammatory bowel disease, rheumatoid arthritis, asthma, ulcerative colitis and Crohn&#39;s disease.

[0001] This claims the benefit of U.S. Provisional application No.60/171,969, filed Dec. 23, 1999 and U.S. Provisional application No.60/213,341 filed Jun. 22, 2000.

BACKGROUND OF THE INVENTION

[0002] The teachings of all of the references cited herein areincorporated in their entirety herein by reference.

[0003] Inflammation normally is a localized, protective response totrauma or microbial invasion that destroys, dilutes, or walls-off theinjurious agent and the injured tissue. It is characterized in the acuteform by the classic signs of pain, heat, redness, swelling, and loss offunction. Microscopically, it involves a complex series of events,including dilation of arterioles, capillaries, and venules, withincreased permeability and blood flow, exudation of fluids, includingplasma proteins, and leukocyte migration into the area of inflammation.

[0004] Diseases characterized by inflammation are significant causes ofmorbidity and mortality in humans. Commonly, inflammation occurs as adefensive response to invasion of the host by foreign, particularlymicrobial, material. Responses to mechanical trauma, toxins, andneoplasia also may results in inflammatory reactions. The accumulationand subsequent activation of leukocytes are central events in thepathogenesis of most forms of inflammation. Deficiencies of inflammationcompromise the host. Excessive inflammation caused by abnormalrecognition of host tissue as foreign or prolongation of theinflammatory process may lead to inflammatory diseases as diverse asdiabetes, arteriosclerosis, cataracts, reperfusion injury, and cancer,to post-infectious syndromes such as in infectious meningitis, rheumaticfever, and to rheumatic diseases such as systemic lupus erythematosusand rheumatoid arthritis. The centrality of the inflammatory response inthese varied disease processes makes its regulation a major element inthe prevention control or cure of human disease.

[0005] An important cytokine in the inflammatory process isinterleukin-8 (IL-8). IL-8 is a chemokine. It was identified as anagonist for neutrophils on the basis of two effects, chemotaxis and therelease of granule enzymes. IL-8 binds to two receptors on neutrophils.IL-8 receptors are also found on monocytes, basophils, and eosinophils.In human fibroblasts, cytomegalovirus has been shown to induce theexpression of IL-8 receptors and to replicate more rapidly when cellsare exposed to IL-8. IL-8 is a potent chemoattractant for neutrophils;and the early stages of periodontal disease are characterized by theinflux of neutrophils. IL-8 is a potent inducer of angiogenesis inseveral angiogenesis-dependent chronic inflammatory conditions,including rheumatoid arthritis, psoriasis, and idiopathic pulmonaryfibrosis. Additionally, IL-8 is an important source of angiogenicactivity in human lung cancer. Also, IL-8 expression correlates withexperimental metastatic activity of some melanoma cell lines. Thus, aneffective method to treat inflammatory diseases would be to administeran agent that would inhibit IL-8.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIGS. 1-8 are schematic representations of a representativenumber of embodiments of the IL-20 soluble receptor.

DESCRIPTION OF THE INVENTION

[0007] The present invention fills this need by providing for a methodfor treating inflammation in which IL-20 plays a role, comprisingadministering to a mammal in need of treatment of inflammation anantagonist to IL-20 or an antagonist to the IL-20 receptor. Theantagonist to IL-20 can be an antibody, antibody fragment orsingle-chain antibody that binds to IL-20, a soluble receptor that bindsto IL-20. The antagonist to the IL-20 receptor can be an antibody,antibody fragment, single-chain antibody or small molecule that binds tothe IL-20 receptor. Also an anti-sense nucleotide that binds to the mRNAthat encodes IL-20 can be used as an antagonist. We have shown thatIL-20 up-regulates IL-8. Inflammatory diseases in which IL-8 plays asignificant role, and for which a decrease in IL-8 would be beneficialare, adult respiratory disease (ARD), septic shock, multiple organfailure, inflammatory lung injury such as asthma or bronchitis,bacterial pneumonia, psoriasis and inflammatory bowel disease such asulcerative colitis and Crohn's disease, eczema, atopic dermatitis andcontact dermatitis. Thus, antagonists to IL-20 can be used to treatthese diseases.

[0008] The teachings of all the references cited herein are incorporatedin their entirety by reference.

[0009] Definitions

[0010] Prior to setting forth the invention in detail, it may be helpfulto the understanding thereof to define the following terms.

[0011] The terms “amino-terminal” and “carboxyl-terminal” are usedherein to denote positions within polypeptides. Where the contextallows, these terms are used with reference to a particular sequence orportion of a polypeptide to denote proximity or relative position. Forexample, a certain sequence positioned carboxyl-terminal to a referencesequence within a polypeptide is located proximal to the carboxylterminus of the reference sequence, but is not necessarily at thecarboxyl terminus of the complete polypeptide.

[0012] The term “complement/anti-complement pair” denotes non-identicalmoieties that form a non-covalently associated, stable pair underappropriate conditions. For instance, biotin and avidin (orstreptavidin) are prototypical members of a complement/anti-complementpair. Other exemplary complement/anti-complement pairs includereceptor/ligand pairs, antibody/antigen (or hapten or epitope) pairs,sense/antisense polynucleotide pairs, and the like. Where subsequentdissociation of the complement/anti-complement pair is desirable, thecomplement/anti-complement pair preferably has a binding affinity of<10⁹M⁻¹.

[0013] The term “complements of a polynucleotide molecule” is apolynucleotide molecule having a complementary base sequence and reverseorientation as compared to a reference sequence. For example, thesequence 5′ ATGCACGGG 3′ is complementary to 5′ CCCGTGCAT 3 ′.

[0014] The term “contig” denotes a polynucleotide that has a contiguousstretch of identical or complementary sequence to anotherpolynucleotide. Contiguous sequences are said to “overlap” a givenstretch of polynucleotide sequence either in their entirety or along apartial stretch of the polynucleotide. For example, representativecontigs to the polynucleotide sequence 5′-ATGGCTTAGCTT-3′ are5′-TAGCTTgagtct-3′ and 3′-gtcgacTACCGA-5 ′.

[0015] The term “degenerate nucleotide sequence” denotes a sequence ofnucleotides that includes one or more degenerate codons (as compared toa reference polynucleotide molecule that encodes a polypeptide).Degenerate codons contain different triplets of nucleotides, but encodethe same amino acid residue (i.e., GAU and GAC triplets each encodeAsp).

[0016] The term “expression vector” is used to denote a DNA molecule,linear or circular, that comprises a segment encoding a polypeptide ofinterest operably linked to additional segments that provide for itstranscription. Such additional segments include promoter and terminatorsequences, and may also include one or more origins of replication, oneor more selectable markers, an enhancer, a polyadenylation signal, etc.Expression vectors are generally derived from plasmid or viral DNA, ormay contain elements of both.

[0017] The term “isolated”, when applied to a polynucleotide, denotesthat the polynucleotide has been removed from its natural genetic milieuand is thus free of other extraneous or unwanted coding sequences, andis in a form suitable for use within genetically engineered proteinproduction systems. Such isolated molecules are those that are separatedfrom their natural environment and include cDNA and genomic clones.Isolated DNA molecules of the present invention are free of other geneswith which they are ordinarily associated, but may include naturallyoccurring 5′ and 3′ untranslated regions such as promoters andterminators. The identification of associated regions will be evident toone of ordinary skill in the art (see for example, Dynan and Tijan,Nature 316:774-78 (1985).

[0018] An “isolated” polypeptide or protein is a polypeptide or proteinthat is found in a condition other than its native environment, such asapart from blood and animal tissue. In a preferred form, the isolatedpolypeptide is substantially free of other polypeptides, particularlyother polypeptides of animal origin. It is preferred to provide thepolypeptides in a highly purified form, i.e. greater than 95% pure, morepreferably greater than 99% pure. When used in this context, the term“isolated” does not exclude the presence of the same polypeptide inalternative physical forms, such as dimers or alternatively glycosylatedor derivatized forms.

[0019] The term “operably linked”, when referring to DNA segments,indicates that the segments are arranged so that they function inconcert for their intended purposes, e.g., transcription initiates inthe promoter and proceeds through the coding segment to the terminator.

[0020] A “polynucleotide” is a single- or double-stranded polymer ofdeoxyribonucleotide or ribonucleotide bases read from the 5′ to the 3′end. Polynucleotides include RNA and DNA, and may be isolated fromnatural sources, synthesized in vitro, or prepared from a combination ofnatural and synthetic molecules. Sizes of polynucleotides are expressedas base pairs (abbreviated “bp”), nucleotides (“nt”), or kilobases(“kb”). Where the context allows, the latter two terms may describepolynucleotides that are single-stranded or double-stranded. When theterm is applied to double-stranded molecules it is used to denoteoverall length and will be understood to be equivalent to the term “basepairs”. It will be recognized by those skilled in the art that the twostrands of a double-stranded polynucleotide may differ slightly inlength and that the ends thereof may be staggered as a result ofenzymatic cleavage; thus all nucleotides within a double-strandedpolynucleotide molecule may not be paired. Such unpaired ends will ingeneral not exceed 20 nucleotides in length.

[0021] A “polypeptide” is a polymer of amino acid residues joined bypeptide bonds, whether produced naturally or synthetically. Polypeptidesof less than about 10 amino acid residues are commonly referred to as“peptides”.

[0022] The term “promoter” is used herein for its art-recognized meaningto denote a portion of a gene containing DNA sequences that provide forthe binding of RNA polymerase and initiation of transcription. Promotersequences are commonly, but not always, found in the 5′ non-codingregions of genes.

[0023] A “protein” is a macromolecule comprising one or more polypeptidechains. A protein may also comprise non-peptidic components, such ascarbohydrate groups. Carbohydrates and other non-peptidic substituentsmay be added to a protein by the cell in which the protein is produced,and will vary with the type of cell. Proteins are defined herein interms of their amino acid backbone structures; substituents such ascarbohydrate groups are generally not specified, but may be presentnonetheless.

[0024] The term “receptor” denotes a cell-associated protein that bindsto a bioactive molecule (i.e., a ligand) and mediates the effect of theligand on the cell. Membrane-bound receptors are characterized by amulti-domain structure comprising an extracellular ligand-binding domainand an intracellular effector domain that is typically involved insignal transduction. Binding of ligand to receptor results in aconformational change in the receptor that causes an interaction betweenthe effector domain and other molecule(s) in the cell. This interactionin turn leads to an alteration in the metabolism of the cell. Metabolicevents that are linked to receptor-ligand interactions include genetranscription, phosphorylation, dephosphorylation, increases in cyclicAMP production, mobilization of cellular calcium, mobilization ofmembrane lipids, cell adhesion, hydrolysis of inositol lipids andhydrolysis of phospholipids. In general, receptors can be membranebound, cytosolic or nuclear, monomeric (e.g., thyroid stimulatinghormone receptor, beta-adrenergic receptor) or multimeric (e.g., PDGFreceptor, growth hormone receptor, IL-3 receptor, GM-CSF receptor, G-CSFreceptor, erythropoietin receptor and IL-6 receptor).

[0025] The term “secretory signal sequence” denotes a DNA sequence thatencodes a polypeptide (a “secretory peptide”) that, as a component of alarger polypeptide, directs the larger polypeptide through a secretorypathway of a cell in which it is synthesized. The larger polypeptide iscommonly cleaved to remove the secretory peptide during transit throughthe secretory pathway.

[0026] Molecular weights and lengths of polymers determined by impreciseanalytical methods (e.g., gel electrophoresis) will be understood to beapproximate values. When such a value is expressed as “about” X or“approximately” X, the stated value of X will be understood to beaccurate to ±10%.

[0027] Introduction

[0028] The present invention relates to the treatment of inflammationand inflammatory diseases in which IL-20 plays a role either ininitiating or spreading or maintenance by administering to the afflictedindividual an antagonist to IL-20. That antagonist can be an antibody toIL-20, a soluble receptor that binds to IL-20, an anti-sense molecule oran antibody that binds to either the IL-20RA subunit or the IL-20RBsubunit of the IL-20 receptor.

[0029] IL-20 is defined and methods for producing it and antibodies toIL-20 are contained in International Patent Application No.PCT/US98/25228, publication No. WO 99/27103, published Nov. 25, 1998 andU.S. Pat. Application Ser. No. 9,313,458 filed May 17, 1999. Thepolynucleotide and polypeptide of human IL-20 are represented by SEQ IDNos.: 1-4, and mouse IL-20 by SEQ ID N0s.: 5-9.

[0030] The receptor to IL-20 has been discovered and is a heterodimercomprised of the polypeptide termed ‘IL-20RA’ (formally called Zcytor7)and a polypeptide termed ‘IL-20RB’. The IL-20RA polypeptide, nucleicacid that encodes it, antibodies to IL-20RA, and methods for producingit are disclosed in U.S. Pat. No. 5,945,511 issued Aug. 31, 1999. SEQ IDNos.: 10-12 are the IL-20RA polynucleotides and polypeptides. Theextracellular domain of the human IL-20RA is comprised of a polypeptideselected from the group consisting of SEQ ID Nos.: 12, 55, 63 and 65,the full-length receptor subunit being comprised of SEQ ID No.: 11. Theextracellular domain of mouse IL-20RA is SEQ ID No.: 38, SEQ ID No.: 37being the entire mouse IL-20RA.

[0031] The extracellular domain of IL-20RB (SEQ ID Nos.: 13-14, and avariant SEQ ID Nos.: 18 and 19) is comprised of a polypeptide selectedfrom the group consisting of SEQ ID Nos.: 15, 59, 61, 67, 68 and 69.Preferably, the extracellular domain of the IL-20RA polypeptide and theextracellular domain of the IL-20RB polypeptide are covalently linkedtogether. In a preferred embodiment one extracellular subunitpolypeptide has a constant region of a heavy chain of an immunoglobulinfused to its carboxy terminus and the other extracellular subunit has aconstant light chain of an immunoglobulin (Ig) fused to its carboxyterminus such that the two polypeptides come together to form a solublereceptor and a disulfide bond is formed between the heavy and the lightIg chains. In another method, a peptide linker could be fused to the twocarboxy-termini of the polypeptides to form a covalently bonded solublereceptor.

[0032] SEQ ID Nos.: 22 and 23 are constructs of the extracellular domainof IL-20RA fused to a mutated human immunoglobulin gamma 1 constantregion produced according to the procedure set forth in example 5. SEQID No.: 62 is the predicted mature sequence without the signal sequence.SEQ ID Nos.: 20 and 21 are constructs of the extracellular domain ofIL-20RB fused to wild type human immunoglobulin kappa light chainconstant region produced according to the procedure of example 5. SEQ IDNo.: 60 is the predicted mature sequence without the signal sequence.FIG. 1 depicts the heterotetramer produced by example 5.

[0033] SEQ ID Nos.: 52 and 53 are constructs of the extracellular domainof IL-20RA fused to a mutated human immunoglobulin gamma 1 constantregion produced according to the procedure set forth in example 12. SEQID No.: 54 is the predicted mature sequence without the signal sequence.SEQ ID Nos.: 56 and 57 are constructs of the extracellular domain ofIL-20RB fused to wild type human immunoglobulin kappa light chainconstant region produced according to the procedure of example 12. SEQID No.: 58 is the predicted mature sequence without the signal sequence.The resultant heterotetramer is almost identical to that produced byexample 5, the primary difference being the absence of a polypeptidelinker between the extracellular domains and the beginning of the Igconstant regions, 22 in FIG. 1. Hereinafter, the term “extracellulardomain of a receptor” means the extracellular domain of the receptor ora portion of the extracellular domain that is necessary for binding toits ligand, in this case the ligand being IL-20.

[0034] One can link together the extracellular domains of IL-20RA andIL-20RB in a number of ways such that the resultant soluble receptor canbind to IL-20. FIGS. 1-8 illustrate a representative number ofembodiments of the present invention. Common elements in each of thedrawings are given the same number. FIG. 1 represents the embodiment ofthe present invention produced according to example 5 below. The solublereceptor construct, designated 10, is comprised of two IL-20 bindingsite polypeptide chains designated 12 and 14. Each binding site iscomprised of the extracellular domain of IL-20RA, designated 16, and theextracellular domain of IL-20RB designated 18.

[0035] The extracellular domain, 16, of IL-20RA is linked to theconstant heavy one (CH1) domain, 20, of the human immunoglobulin gamma 1heavy chain constant region via linker 22, which is SEQ ID No.:72. TheCH1 domain, 20, is then linked to the CH2 domain, 24, via hinge region23. The CH2 domain, 24, is linked to the CH3 domain, 26, via hingeregion 25.

[0036] Comparing the construct of FIG. 1 with SEQ ID No.:22, theextracellular domain, 16, of IL-20RA extends from amino acid residues36, a valine, to and including amino acid residue 249, a glutamine ofSEQ ID No.:22. Polypeptide linker, 22, extends from amino acid residue250, a glycine to and including amino acid residue 264, a serine, of SEQID No.:22. The CH1 domain, 22 of FIG. 1, extends from amino acid residue265, an alanine, to and including amino acid residue 362, a valine, ofSEQ ID No.:22. Hinge region 23 of FIG. 1 extends from amino acid residue363, a glutamic acid to and including amino acid residue 377, a proline,of SEQ ID No.: 22. Chains 12 and 14 are disulfide-bonded together bymeans of disulfide bonds 28 and 30. The disulfide bonds are formedbetween the heavy chains by the cysteine residues at positions 373 and376 of SEQ ID No.: 22 of each of the two heavy chains.

[0037] Extracellular domain, 18, of IL-20RB is linked to the constantregion of the human kappa light chain (CL), 34 of FIG. 1 via polypeptidelinker 32, which is the polypeptide SEQ ID No.: 72. The extracellulardomain, 18, of IL-20RB extends from amino acid residue 30, a valine, toand including amino acid residue 230, an alanine, of SEQ ID No.: 20.Polypeptide linker, 32, extends from amino acid residue 231, a glycine,to and including amino acid residue 245, a serine, of SEQ ID No.:20. Thekappa constant light region, 34, extends from amino acid residue 246, anarginine, to and including the final amino acid residue 352, a cysteine,of SEQ ID No.:20. The cysteine at position 352 of SEQ ID No.: 20 forms adisulfide bond, 36 in FIG. 1, with the cysteine at position 367 of SEQID No.: 22. The constant light chain 34 is thus linked to the hingeregion, 23, by disulfide bond, 36. In this way, the extracellulardomain, 16, of IL-20RA is linked to the extracellular domain, 18, ofIL-20RB to form a soluble receptor.

[0038] If the cysteine residues at positions 373 and 376 of SEQ IDNo.:22 were changed to different amino acid residues, the two IL-20binding polypeptides, 12 and 14, would not be disulfide bonded togetherand would form a construct shown in FIG. 2 having hinge region, 27.

[0039]FIG. 3 shows a very simple soluble receptor 38 of the presentinvention wherein extracellular domain, 16, of IL-20RA is connected tothe extracellular domain, 18, of IL-20RB by means of a polypeptidelinker, 40. The polypeptide linker extends from the amino terminus ofextracellular domain, 16, of IL-20RA and is connected to the carboxylterminus of the extracellular domain, 18, of IL-20RB. The polypeptidelinker should be between 100-240 amino acids in length, preferably about170 amino acid residues in length. A suitable linker would be comprisedof glycine and serine residues. A possible linker would be multipleunits of SEQ ID No.: 72, preferably about 12.

[0040]FIG. 4 shows an embodiment that has the extracellular domain, 16,of IL-20RA linked to the extracellular domain, 18, of IL-20RB by meansof linker 40, as in FIG. 3. While the extracellular domain, 16, ofIL-20RA is linked to the CH1 domain, 20, as in FIG. 1 by means ofpolypeptide linker 42, which should be about 30 amino acid residues inlength. An ideal linker would be comprised of glycine and serine as inSEQ ID No.: 72, and the hinge sequence, 23 of FIG. 1.

[0041]FIG. 5 shows another possible embodiment of the present invention.In this embodiment, a polypeptide linker 44 of about 15 amino acidresidue, e.g. SEQ ID No.: 72, links the carboxyl terminus of theextracellular domain, 18, of IL-20RB with the amino terminus of theextracellular domain, 16, of IL-20RA. A polypeptide linker 46 of about30 amino acid residues extends from the carboxy terminus of theextracellular domain, 16, of IL-20RA to the CH2 domain. The carboxylterminus of linker 46 would preferably be comprised of the hinge regionextending from amino acid residue 363, a glutamic acid to and includingamino acid residue 377, a proline, of SEQ ID No.: 22. Nonetheless,polypeptide linker 46 would ideally have at least one cysteine residueat its carboxyl terminus so a disulfide bond could be formed.

[0042] The soluble IL-20 receptor of FIG. 6 is identical to that of FIG.1 except for the CH3 domain, 26 of FIG. 1, is not present on theembodiment of FIG. 6. The CH3 region begins at amino acid residue 488, aglycine, and extends to the last residue 594 of SEQ ID No.: 22.

[0043]FIG. 7 shows a soluble IL-20 receptor construct that is identicalto the construct of FIG. 1 except both the CH2, and CH3 domains areabsent. The CH2 and CH3 domains run from amino acid residue 378, analanine, to the end of the polypeptide sequence of SEQ ID No.: 22.

[0044]FIG. 8 shows a construct wherein both IL-20RA, 16, and IL-20RBhave a polypeptide linker, 48, fused to their respective carboxyltermini. Each polypeptide linker has two cysteine residues such thatwhen they are expressed the cysteines form two disulfide bonds, 50 and52. In this case the polypeptide linker is comprised of the hingeregion, 23 in FIG. 1. The hinge region is comprised of amino acidresidues 363, a glutamine, to and including amino acid residue 377 ofSEQ ID No.: 22.

[0045] In another aspect of the invention, a method is provided forproducing a soluble receptor comprised of extracellular domains ofIL-20RA and IL-20RB comprising (a) introducing into a host cell a firstDNA sequence comprised of a transcriptional promoter operatively linkedto a first secretory signal sequence followed downstream by and inproper reading frame the DNA that encodes the extracellular portion ofIL-20RA and the DNA that encodes an immunoglobulin light chain constantregion;(b) introducing into the host cell a second DNA constructcomprised of a transcriptional promoter operatively linked to a secondsecretory signal followed downstream by and in proper reading frame aDNA sequence that encodes the extracellular portion of IL-20RB and a DNAsequence that encodes an immunoglobulin heavy chain constant regiondomain selected from the group consisting of C_(H)1, C_(H)2, C_(H)3 andC_(H)4; (c) growing the host cell in an appropriate growth medium underphysiological conditions to allow the secretion of a fusion proteincomprised of the extracellular domain of IL-20RA and IL-20RB; and (d)isolating the polypeptide from the host cell. In one embodiment, thesecond DNA sequence further encodes an immunoglobulin heavy chain hingeregion wherein the hinge region is joined to the heavy chain constantregion domain. In another embodiment, the second DNA sequence furtherencodes an immunoglobulin variable region joined upstream of and inproper reading frame with the immunoglobulin heavy chain constantregion.

[0046] In an alternative embodiment, a method is provided for producinga soluble receptor comprised of the extracellular domains of IL-20RA andIL-20RB comprising (a) introducing into a host cell a first DNA sequencecomprised of a transcriptional promoter operatively linked to a firstsecretory signal sequence followed downstream by and in proper readingframe the DNA that encodes the extracellular portion of IL-20RB and theDNA that encodes an immunoglobulin light chain constant region;(b)introducing into the host cell a second DNA construct comprised of atranscriptional promoter operatively linked to a second secretory signalfollowed downstream by and in proper reading frame a DNA sequence thatencodes the extracellular portion of IL-20RA and a DNA sequence thatencodes an immunoglobulin heavy chain constant region domain selectedfrom the group consisting of C_(H)1, C_(H)2, C_(H)3 and C_(H)4; (c)growing the host cell in an appropriate growth medium underphysiological conditions to allow the secretion of a dimerizedheterodimeric fusion protein comprised of the extracellular domain ofIL-20RA and IL-20RB; and (d) isolating the dimerized polypeptide fromthe host cell. In one embodiment, the second DNA sequence furtherencodes an immunoglobulin heavy chain hinge region wherein the hingeregion is joined to the heavy chain constant region domain. In anotherembodiment, the second DNA sequence further encodes an immunoglobulinvariable region joined upstream of and in proper reading frame with theimmunoglobulin heavy chain constant region. (See U.S. Pat. No.5,843,725.) As used herein, the term “antibodies” includes polyclonalantibodies, affinity-purified polyclonal antibodies, monoclonalantibodies, and antigen-binding fragments, such as F(ab′)₂ and Fabproteolytic fragments. Genetically engineered intact antibodies orfragments, such as chimeric antibodies, Fv fragments, single chainantibodies and the like, as well as synthetic antigen-binding peptidesand polypeptides, are also included. Non-human antibodies may behumanized by grafting non-human CDRs onto human framework and constantregions, or by incorporating the entire non-human variable domains(optionally “cloaking” them with a human-like surface by replacement ofexposed residues, wherein the result is a “veneered” antibody). In someinstances, humanized antibodies may retain non-human residues within thehuman variable region framework domains to enhance proper bindingcharacteristics. Through humanizing antibodies, biological half-life maybe increased, and the potential for adverse immune reactions uponadministration to humans is reduced. The binding affinity of an antibodycan be readily determined by one of ordinary skill in the art, forexample, by Scatchard analysis. A variety of assays known to thoseskilled in the art can be utilized to detect antibodies that bind toprotein or peptide. Exemplary assays are described in detail inAntibodies: A Laboratory Manual, Harlow and Lane (Eds.) (Cold SpringHarbor Laboratory Press, 1988). Representative examples of such assaysinclude: concurrent immunoelectrophoresis, radioimmunoassay,radioimmuno-precipitation, enzyme-linked immunosorbent assay (ELISA),dot blot or Western blot assay, inhibition or competition assay, andsandwich assay.

[0047] We have shown that IL-20 up-regulates IL-8. Inflammatory diseasesin which IL-8 plays a significant role, and for which a decrease in IL-8would be beneficial are, adult respiratory disease (ARD), septic shock,multiple organ failure, inflammatory lung injury such as asthma orbronchitis, bacterial pneumonia, psoriasis and inflammatory boweldisease such as ulcerative colitis and Crohn's disease, eczema, atopicdermatitis and contact dermatitis. Thus, antagonists to IL-20 can beused to treat these diseases.

[0048] Biology of IL-20, Its receptor and Its Role in Psoriasis

[0049] Two orphan class II cytokine receptors, both of which areexpressed in skin, were identified as IL-20 receptor subunits. BothIL-20 receptor subunits are required for ligand binding, distinguishingtheir role from that of subunits in the four other known class IIcytokine receptors. IL-20RA and IL-20RB are also coexpressed in a numberof human tissues besides skin, including ovary, adrenal gland, testis,salivary gland, muscle, lung, kidney, heart and to a lesser degree thesmall intestine suggesting additional target tissues for IL-20 action.Additionally, we have detected IL-20RA mRNA but not IL-20RB mRNA inseveral human tissues including stomach, thyroid, pancreas, uterus,brain and prostate suggesting that IL-20RA may partner with other classII receptor subunits. We conclude that the IL-20 heterodimeric receptoris structurally similar to other class II cytokine receptors and isexpressed in skin where we have demonstrated activity of the IL-20ligand.

[0050] Two lines of evidence indicate that a role IL-20 and its receptorare involved in psoriasis. This multigenic skin disease is characterizedby increased keratinocyte proliferation, altered keratinocytedifferentiation, and infiltration of immune cells into the skin. Thefirst line of evidence for a role of IL-20 in psoriasis is that theobserved hyperkeratosis and thickened epidermis in the transgenic micethat resemble human psoriatic abnormalities. Decreased numbers oftonofilaments, thought to be related to defective keratinization, are astriking feature of human psoriasis. Intramitochondrial inclusions havebeen found in both chemically induced and naturally occurringhyperplastic skin conditions in mice. The cause of the inclusions andtheir effects on mitochondrial function, if any, are unknown. Weconclude that IL-20 transgenic mice exhibit many of the characteristicsobserved in human psoriasis.

[0051] A second line of evidence that implicates the IL-20 receptor inpsoriasis is that both IL-20RA and IL-20RB mRNA are markedly upregulatedin human psoriatic skin compared to normal skin. Both IL-20 receptorsubunits are expressed in keratinocytes throughout the epidermis and arealso expressed in a subset of immune and endothelial cells. We proposethat increased expression of an activated IL-20 receptor may alter theinteractions between endothelial cells, immune cells and keratinocytes,leading to dysregulation of keratinocyte proliferation anddifferentiation.

[0052] A crucial step in understanding the function of a novel cytokineis the identification and characterization of its cognate receptor. Wehave successfully used a structure-based approach to isolate a novelinterleukin that ultimately led to the isolation of its receptor. IL-20stimulates signal transduction in the human keratinocyte HaCaT cellline, supporting a direct action of this novel ligand in skin. Inaddition, IL-1β, EGF and TNF-β, proteins known to be active inkeratinocytes and to be involved with proliferative and pro-inflammatorysignals in skin, enhance the response to IL-20. In both HaCaT and BHKcells expressing the IL-20 receptor, IL-20 signals through STAT3.

[0053] Use of Antagonist to IL-20 to Treat Psoriasis

[0054] As indicated in the discussion above and the examples below,IL-20 is involved in the pathology of psoriasis. The present inventionis in particular a method for treating psoriasis by administeringantagonists to IL-20. The antagonists to IL-20 can either be a solublereceptor that binds to IL-20 or antibodies, single chain antibodies orfragments of antibodies that bind to either IL-20 or the IL-20 receptor.The antagonists will thus prevent activation of the IL-20 receptor.

[0055] Psoriasis is one of the most common dermatologic diseases,affecting up to 1 to 2 percent of the world's population. It is achronic inflammatory skin disorder characterized by erythematous,sharply demarcated papules and rounded plaques, covered by silverymicaceous scale. The skin lesions of psoriasis are variably pruritic.Traumatized areas often develop lesions of psoriasis. Additionally,other external factors may exacerbate psoriasis including infections,stress, and medications, e.g. lithium, beta blockers, andanti-malarials.

[0056] The most common variety of psoriasis is called plaque type.Patients with plaque-type psoriasis will have stable, slowly growingplaques, which remain basically unchanged for long periods of time. Themost common areas for plaque psoriasis to occur are the elbows knees,gluteal cleft, and the scalp. Involvement tends to be symmetrical.Inverse psoriasis affects the intertriginous regions including theaxilla, groin, submammary region, and navel, and it also tends to affectthe scalp, palms, and soles. The individual lesions are sharplydemarcated plaques but may be moist due to their location. Plaque-typepsoriasis generally develops slowly and runs an indolent course. Itrarely spontaneously remits.

[0057] Eruptive psoriasis (guttate psoriasis) is most common in childrenand young adults. It develops acutely in individuals without psoriasisor in those with chronic plaque psoriasis. Patients present with manysmall erythematous, scaling papules, frequently after upper respiratorytract infection with beta-hemolytic streptococci. Patients withpsoriasis may also develop pustular lesions. These may be localized tothe palms and soles or may be generalized and associated with fever,malaise, diarrhea, and arthralgias.

[0058] About half of all patients with psoriasis have fingernailinvolvement, appearing as punctate pitting, nail thickening or subungualhyperkeratosis. About 5 to 10 percent of patients with psoriasis haveassociated joint complaints, and these are most often found in patientswith fingernail involvement. Although some have the coincidentoccurrence of classic Although some have the coincident occurrence ofclassic rheumatoid arthritis, many have joint disease that falls intoone of five type associated with psoriasis: (1) disease limited to asingle or a few small joints (70 percent of cases); (2) a seronegativerheumatoid arthritis-like disease; (3) involvement of the distalinterphalangeal joints; (4) severe destructive arthritis with thedevelopment of “arthritis mutilans”; and (5) disease limited to thespine.

[0059] Psoriasis can be treated by administering antagonists to IL-20.The preferred antagonists are either a soluble receptor to IL-20 orantibodies, antibody fragments or single chain antibodies that bind toeither the IL-20 receptor or to IL-20. The antagonists to IL-20 can beadministered alone or in combination with other established therapiessuch as lubricants, keratolytics, topical corticosteroids, topicalvitamin D derivatives, anthralin, systemic antimetabolites such asmethotrexate, psoralen-ultraviolet-light therapy (PUVA), etretinate,isotretinoin, cyclosporine, and the topical vitamin D3 derivativecalcipotriol. The antagonists, in particularly the soluble receptor orthe antibodies that bind to IL-20 or the IL-20 receptor can beadministered to individual subcutaneously, intravenously, ortransdermally using a cream or transdermal patch that contains theantagonist of IL-20. If administered subcutaneously, the antagonist canbe injected into one or more psoriatic plaques. If administeredtransdermally, the antagonists can be administered directly on theplaques using a cream containing the antagonist to IL-20.

[0060] Use of Antagonists to IL-20 to Treat Inflammatory Conditions ofthe Lung.

[0061] Antagonists to IL-20 can be administered to a person who hasasthma, bronchitis or cystic fibrosis or other inflammatory lung diseaseto treat the disease. The antagonists can be administered by anysuitable method including intravenous, subcutaneous, bronchial lavage,and the use of inhalant containing an antagonist to IL-20.

[0062] Administration of Antagonists to IL-20

[0063] The quantities of antagonists to IL-20 necessary for effectivetherapy will depend upon many different factors, including means ofadministration, target site, physiological state of the patient, andother medications administered. Thus, treatment dosages should betitrated to optimize safety and efficacy. Typically, dosages used invitro may provide useful guidance in the amounts useful for in vivoadministration of these reagents. Animal testing of effective doses fortreatment of particular disorders will provide further predictiveindication of human dosage. Methods for administration include oral,intravenous, peritoneal, intramuscular, transdermal or administrationinto the lung or trachea in spray form by means or a nebulizer oratomizer. Pharmaceutically acceptable carriers will include water,saline, buffers to name just a few. Dosage ranges would ordinarily beexpected from 1 μg to 1000 μg per kilogram of body weight per day. Adosage for an average adult of the IL-20 soluble receptor would be about25 mg given twice weekly as a subcutaneous injection. A dosage of anantibody that binds to the IL-20 would be about 25 mg given twiceweekly. A mixture of antibodies that bind to the IL-20RA and IL-20RBsubunits would be about 25 mg given twice weekly for an adult.Injections could be given at the site of psoriatic lesions for thetreatment of psoriasis. For subcutaneous or intravenous administrationof the antagonist to IL-20, the antibody or soluble receptor can be inphosphate buffered saline. Also in skin diseases such as psoriasis, theantagonist to IL-20 can be administered via an ointment or transdermalpatch. The doses by may be higher or lower as can be determined by amedical doctor with ordinary skill in the art. For a complete discussionof drug formulations and dosage ranges see Remington's PharmaceuticalSciences, 18^(th) Ed., (Mack Publishing Co., Easton, Pa., 1996), andGoodman and Gilman's: The Pharnacological Bases of Therapeutics, 9^(th)Ed. (Pergamon Press 1996).

[0064] The invention is further illustrated by the followingnon-limiting examples.

EXAMPLE 1 Up-regulation of IL-8 by IL-20

[0065] Methods:

[0066] Normal Human Epidermal neonatal keratinocytes (NHEK) (fromClonetics) at passage 2 were plated and grown to confluency in 12 welltissue culture plates. KGM (Keratinocyte growth media) was purchasedfrom Clonetics. When cells reached confluency, they were washed with KGMmedia minus growth factors =KBM (keratinocyte basal media). Cells wereserum starved in KBM for 72 hours prior to the addition of testcompounds. Thrombin at 1 I.U./mL and trypsin at 25 nM were used aspositive controls. One mL of media/well was added. KBM only was used asthe negative control.

[0067] IL-20 was made up in KBM media and added at varyingconcentrations, from 2.5 μg/ml down to 618 ng/mL in a first experimentand from 2.5 μg/mL down to 3 ng/mL in a second experiment.

[0068] Cells were incubated at 37° C., 5% CO₂ for 48 hours. Supernatantswere removed and frozen at −80° C. for several days prior to assayingfor IL-8 and GM-CSF levels. Human IL-8 Immunoassay kit # D8050 (RandDSystems, Inc.) and human GM-CSF Immunoassay kit # HSGMO (RandD Systems,Inc.) were used to determine cytokine production followingmanufacturer's instructions.

[0069] Results

[0070] The results indicated that the expression of IL-8 and GM-CSF wereinduced by IL-20.

EXAMPLE 2 Cloning of IL-20RB

[0071] Cloning of IL-20RB coding region

[0072] Two PCR primers were designed based on the sequence fromInternational Patent Application No. PCT/US99/03735 (publication No. WO99/46379) filed on Mar. 8, 1999. SEQ ID No.: 16 contains the ATG (Met 1)codon with an EcoRI restriction site, SEQ ID No.: 17 contains the stopcodon (TAG) with an XhoI restriction site. The PCR amplification wascarried out using a human keratinocyte (HaCaT) cDNA library DNA as atemplate and SEQ ID No.: 16 and SEQ ID No.: 17 as primers. The PCRreaction was performed as follows: incubation at 94° C. for 1 minfollowed by 30 cycles of 94° C. for 30 sec and 68° C. for 2 min, afteradditional 68° C. for 4 min, the reaction was stored at 4° C. The PCRproducts were run on 1% Agarose gel, and a 1 kb DNA band was observed.The PCR products were cut from the gel and the DNA was purified using aQIAquick Gel Extraction Kit (Qiagen). The purified DNA was digested withEcoRI and XhoI, and cloned into a pZP vector that was called pZP7N. ApZP plasmid is a mammalian expression vector containing an expressioncassette having the mouse metallothionein- 1 promoter, human tPA leaderpeptide, multiple restriction sites for insertion of coding sequences, aGlu-Glu tag, and a human growth hormone terminator. The plasmid also hasan E. coli origin of replication, a mammalian selectable markerexpression unit having an SV40 promoter, an enhancer and an origin ofreplication, as well as a DHFR gene, and the SV40 terminator. SeveralIL-20RB-pZP7N clones were sequenced. They all contain threenon-conservative mutations compared with the sequence of IL-20RB inPCT/US99/03735: (sequence IL-20RB-pZP7N), 146 Pro (CCC)—Thr (ACC), 148His (CAT) —Asp (GAT), and 171 Thr (ACG)—Arg (AGG).

[0073] To verify the three substitutions in IL-20RB-pZP7N clone, PCRamplification was carried out using three difference cDNA sources —fetalskin marathon cDNA, HaCaT cDNA library DNA, and prostate smooth musclecDNA library DNA —as templates. The PCR products were gel purified andsequenced. The sequence of each of the three PCR products was consistentwith that of the IL-20RB-pZP7N clone. IL-20RB is SEQ ID No.: 13 and 14,and the mature extracellular domain is SEQ ID No.: 15.

EXAMPLE 3 Binding of IL-20 to IL-20RB/IL-20RA Heterodimer

[0074] A cell-based binding assay was used to verify IL-20 binds toIL-20RA-IL-20RB heterodimer.

[0075] Expression vectors containing known and orphan Class II cytokinereceptors (including IL-20RA and IL-20RB) were transiently transfectedinto COS cells in various combinations, which were then assayed fortheir ability to bind biotin-labeled IL-20 protein. The results showIL-20RB- IL-20RA heterodimer is a receptor for IL-20. The procedure usedis described below.

[0076] The COS cell transfection was performed in a 12-well tissueculture plate as follows: 0.5 μg DNA was mixed with medium containing 5μl lipofectamine in 92 μl serum free Dulbecco's modified Eagle's medium(DMEM) (55 mg sodium pyruvate, 146 mg L-glutamine, 5 mg transferrin, 2.5mg insulin, 1 μg selenium and 5 mg fetuin in 500 ml DMEM), incubated atroom temperature for 30 minutes and then added to 400 μl serum free DMEMmedia. This 500 μl mixture was then added to 1.5 ×10⁵ COS cells/well andincubated for 5 hours at 37° C. 500 μl 20% fetal bovine serum (FBS) DMEMmedia was added and incubated overnight.

[0077] The assay, a modification of the “secretion trap” (Davis, S., etal., Cell 87: 1161-1169 (1996), was performed as follows: cells wererinsed with PBS/1% bovine serum albumin (BSA) and blocked for 1 hourwith TNB (0.1 M Tris-HCl, 0.15 M NaCl and 0.5% Blocking Reagent (NENRenaissance TSA-Direct Kit Cat# NEL701) in water). This was followed bya one-hour incubation with 3 μg/ml biotinylated IL-20 protein in TNB.Cells were washed with PBS/1% BSA and incubated for another hour with1:300 diluted streptavidin-HRP (NEN kit) in TNB. Following another wash,cells were fixed for 15 minutes with 1.8% Formaldehyde inphosphate-buffered saline (PBS). Cells were then washed with TNT (0.1 MTris-HCL, 0.15 M NaCL, and 0.05% Tween-20 in water). Positive bindingsignals were detected following a five-minute incubation withfluorescein tyramide reagent diluted 1:50 in dilution buffer (NEN kit).Cells were washed with TNT, preserved with Vectashield Mounting Media(Vector Labs) diluted 1:5 in TNT, and visualized using an FiTC filter onan inverted fluorescent microscope.

EXAMPLE 4 Up-regulation of Inflammatory Cytokines by IL-20

[0078] Cell Treatment

[0079] The human keratinocyte cell line, HaCaT was grown at 37° C. toseveral days post-confluence in T-75 tissue culture flasks. At thispoint, normal growth media (DMEM +10% FBS) was removed and replaced withserum-free media. Cells were then incubated for two days at 37° C. DMEMwas then removed and four flasks of cells per treatment were treatedwith one of each of the following conditions for four hours at 37° C.:recombinant human (rh) IL-1 alpha at 5 ng/mL, rh IL-1 alpha at 20 ng/mL,rh IL-1 alpha at 5 ng/mL +IL-20 at 1 μg/mL, IL-20 at 1 μg/mL, or rhIL-10 at 10 ng/mL.

[0080] RNA Isolation

[0081] Following cytokine treatment, media was removed and cells werelysed using a guanidium thiocyanate solution. Total RNA was isolatedfrom the cell lysate by an overnight spin on a cesium chloride gradient.The following day, the RNA pellet was resuspended in a TE/SDS solutionand ethanol precipitated. RNA was then quantitated using aspectrophotometer, followed by a DNase treatment as per Section V.B. ofClontech's Atlas™ cDNA Expression Arrays User Manual (versionPT3140-1/PR9X390, published Nov. 5, 1999). Quality of RNA samples wasverified by purity calculations based on spec readings, and byvisualization on agarose gel. Genomic contamination of the RNA sampleswas ruled out by PCR analysis of the beta-actin gene.

[0082] Probe Synthesis

[0083] Clontech's protocols for polyA+enrichment, probe synthesis andhybridization to Atlas™ arrays were followed (see above, plus Atlas™Pure Total RNA Labeling System User Manual, PT3231-1/PR96157, publishedJun. 22, 1999). Briefly, polyA+RNA was isolated from 50 mg of total RNAusing streptavidin coated magnetic beads (by Clontech, Paolo Alto,Calif.) and a magnetic particle separator. PolyA+RNA was then labeledwith ^(alpha32)P-dATP via RT-PCR. Clontech CDS primers specific to the268 genes on the Atlas™ human cytokine/receptor array (Cat. #7744-1)were used in the reaction. Labeled probe was isolated using columnchromatography and counted in scintillation fluid.

[0084] Array membrane Hybridization

[0085] Atlas™ arrays were pre-hybridized with Clontech ExpressHyb plus100 mg/mL heat denatured salmon sperm DNA for at least thirty minutes at68° C. with continuous agitation. Membranes were then hybridized with1.9 ×10⁶ CPM/mL (a total of 1.14 ×10⁷ CPM) overnight at 68° C. withcontinuous agitation. The following day, membranes were washed forthirty minutes ×4 in 2×SSC, 1% SDS at 68° C., plus for thirty minutes ×1in 0.1×SSC, 0.5% SDS at 68° C., followed by one final room temperaturewash for five minutes in 2×SSC. Array membranes were then placed inKodak plastic pouches sealed and exposed to a phosphor imager screenovernight at room temperature. The next day, phosphor screens werescanned on a phosphor imager and analyzed using Clontech's AtlasImage™1.0 software.

[0086] Results

Genes Up-regulated by IL-20

[0087] 1. Tumor necrosis factor (TNF) was up-regulated 1.9-2.4 fold byIL-20.

[0088] 2. Placental growth factors 1 & 2 (PLGF) were up-regulated1.9-2.0 fold by IL-20.

[0089] 3. Coagulating factor II receptor was up-regulated 2.0-2.5 foldby IL-20.

[0090] 4. Calcitonin receptor was up-regulated 2.2-2.3 fold by IL-20.

[0091] 5. TNF-inducible hyaluronate-binding protein TSG-6 wasup-regulated 2.1-2.2 fold by IL-20.

[0092] 6. Vascular endothelial growth factor (VEGF) receptor-1precursor, tyrosine-protein kinase receptor (FLT-1) (SFLT) wasup-regulated 2.1-2.7 fold by IL-20.

[0093] 7. MRP-8 (calcium binding protein in macrophages MIF-related) wasup-regulated 2.9-4.1 fold by IL-20.

[0094] 8. MRP-14 (calcium binding protein in macrophages MIF-related)was up-regulated 3.0-3.8 fold by IL-20.

[0095] 9. Relaxin H2 was up-regulated 3.14 fold by IL-20.

[0096] 10. Transforming growth factor beta (TGFβ) receptor III 300 kDawas up-regulated 2.4-3.6 fold by IL-20.

Genes Showing Synergy with IL-20 +IL-1 Treatment

[0097] 1. Bone morphogenic protein 2a was up-regulated 1.8 fold withIL-20 treatment alone, 2.5 fold with IL-1 treatment alone, and 8.2 foldwith both IL-20 and IL-1 treatment together.

[0098] 2. MRP-8 was up-regulated 2.9 fold with IL-20 treatment alone,10.7 fold with IL-1 treatment alone and 18.0 fold with both IL-20 andIL-1 treatment together.

[0099] 3. Erythroid differentiation protein (EDF) was up-regulated 1.9fold with IL-20 treatment alone, 9.7 fold with IL-1 treatment alone and19.0 fold with both IL-20 and IL-1 treatment together.

[0100] 4. MRP-14 (calcium binding protein in macrophages, MIF related)was up-regulated 3.0 fold with IL-20 treatment alone, 12.2 fold withIL-1 treatment alone and 20.3 fold with both IL-20 and IL-1 treatmenttogether.

[0101] 5. Heparin-binding EGF-like growth factor was up-regulated 2.0fold with IL-20 treatment alone, 14 fold with IL-1 treatment alone and25.0 fold with both IL-20 and IL-1 treatment together.

[0102] 6. Beta-thromboglobulin-like protein was up-regulated 1.5 foldwith IL-20 treatment alone, 15 fold with IL-1 treatment alone and 27fold with both IL-20 and IL-1 treatment together.

[0103] 7. Brain-derived neurotrophic factor (BDNF) was up-regulated 1.7fold with IL-20 treatment alone, 25 fold with IL-1 treatment alone and48 fold with both IL-20 and IL-1 treatment together.

[0104] 8. Monocyte chemotactic and activating factor MCAF wasup-regulated 1.3 fold with IL-20 treatment alone, 32 fold with IL-1treatment alone and 56 fold with both IL-20 and IL-1 treatment together.

EXAMPLE 5 IL-20RA/RB receptor-Ig fusion Heterotetramer

[0105] The expression vector pEZE3 was used to express the recombinantIL-20 receptor-Ig fusion protein. The plasmid pEZE3 is derived frompDC312. pDC312 was obtained through license from immunex Corporation.The plasmids pDC312 and pEZE3 contain an EASE segment as described in WO97/25420. The presence of the EASE segment in an expression vector canimprove expression of recombinant proteins two to eight fold in stablecell pools.

[0106] The plasmid pEZE3 is a tricistronic expression vector that may beused to express up to three different proteins in mammalian cells,preferably Chinese Hamster Ovary (CHO) cells. The pEZE3 expression unitcontains the cytomegalovirus (CMV) enhancer/promoter, the adenovirustripartite leader sequence, a multiple cloning site for insertion of thecoding region for the first recombinant protein, the poliovirus type 2internal ribosome entry site, a second multiple cloning site forinsertion of the coding region for the second recombinant protein, anencephalomyocarditis virus internal ribosome entry site, a codingsegment for mouse dihydrofolate reductase, and the SV40 transcriptionterminator. In addition, pEZE3 contains an E. coli origin of replicationand the bacterial beta lactamase gene.

[0107] The IL-20 receptor-Ig fusion protein is a disulfide linkedheterotetramer consisting of two chains of the extracellular domain ofthe human IL-20RB fused to the wild type human immunoglobulin kappalight chain constant region and two chains of the human IL-20RA proteinextracellular domain fused to a mutated human immunoglobulin gamma 1constant region. The human immunoglobulin gamma 1 constant regioncontains amino acid substitutions to reduce FcγRI binding and C 1 qcomplement fixation.

[0108] The human IL-20RB extracellular domain human immunoglobulin kappalight chain constant region fusion construct was generated by overlapPCR. The IL-20RB coding segment consists of amino acids 1 to 230. Thetemplate used for the PCR amplification of the IL-20R segment wasgenerated IL-20RB human kappa light chain constant region expressionconstruct as described below in Example 12. Oligonucleotide primers SEQID No.: 24 and SEQ ID No.: 25 were used to amplify the IL-20RB segment.The entire wild type human immunoglobulin kappa light chain constantregion was used. The template used for the PCR amplification of the wildtype human immunoglobulin kappa light chain constant region segment wasgenerated IL-20RB human kappa light chain constant region expressionconstruct as described in Example 12. Oligonucleotide primers SEQ IDNo.: 26 and SEQ ID No.: 27 were used to amplify the wild type humanimmunoglobulin kappa light chain constant region. The two protein codingdomains were linked by overlap PCR using oligonucleotides SEQ ID No.: 24and SEQ ID No.: 27. A (Gly₄Ser)₃ ( SEQ ID No.: 72) peptide linker wasinserted between the two protein domains. The (Gly₄Ser)₃ peptide linkerwas encoded on the PCR primers SEQ ID No.: 26 and SEQ ID No.:25. Theresultant IL-2ORB extracellular domain/kappa light chain constant regionfusion construct is shown by SEQ ID Nos.: 20 and 21. The predictedmature polypeptide, minus the signal sequence, is SEQ ID No.: 60. Theportion of the extracellular domain of IL-20RB that was actually usedwas comprised of the amino acid sequence of SEQ ID No.: 61. N-terminalsequencing resulted in the predicted amino acid sequence.

[0109] The human IL-20RA extracellular domain human immunoglobulin gamma1 heavy chain constant region fusion construct was generated by overlapPCR of four separate DNA fragments, each generated by separate PCRamplification reactions. The first fragment contained an optimized tPA(tissue plasminogen activator) signal sequence. The tPA signal sequencewas amplified using oligonucleotide primers SEQ ID No.: 28 and SEQ IDNo.: 29 using an in-house previously generated expression vector as thetemplate. The second fragment contained the IL-20RA extracellulardomain-coding region consisting of amino acids 30 to 243 of SEQ ID No.:11. Oligonucleotide primers SEQ ID No.: 30 and SEQ ID No.: 31 were usedto amplify this IL-20RA segment using a previously generated clone ofIL-20RA as the template.

[0110] The human gamma 1 heavy chain constant region was generated from2 segments. The first segment containing the C_(H)1 domain was amplifiedusing oligonucleotide primers SEQ ID No.: 32 and SEQ ID No.: 33 using aclone of the wild type human gamma 1 heavy chain constant region as thetemplate. The second segment containing the remaining hinge, C_(H)2, andC_(H)3 domains of the human immunoglobulin gamma 1 heavy chain constantregion was generated by PCR amplification using oligonucleotide primersSEQ ID No.: 34 and SEQ ID No.: 35. The template used for this PCRamplification was from a previously generated human gamma 1 Fc constructthat contained codons for amino acid substitutions to reduce FcγRIbinding and C1 q complement fixation as described in Example 12.

[0111] The four protein coding domains were linked by overlap PCR usingoligonucleotides SEQ ID No.: 28 and SEQ ID No.: 35. A (Gly₄Ser)₃ peptidelinker was inserted between the IL-20RA and CH1 protein domains. The(Gly₄Ser)₃ peptide linker was encoded on the PCR primers SEQ ID No.: 32and SEQ ID No.: 31. The IL-20RA extracellular domain/domain humanimmunoglobulin gamma 1 heavy constant region fusion protein and DNAsequence are shown in SEQ ID Nos.: 22 and 23. The predicted maturepolypeptide sequence, minus the signal sequence, is SEQ ID No.: 62. Theportion of extracellular domain of IL-20RA that was actually used wascomprised of SEQ ID No.: 63.

[0112] The IL-20RB extracellular domain human immunoglobulin kappa lightchain constant region fusion coding segment was cloned into the secondMCS while the human IL-20RA extracellular domain human immunoglobulingamma 1 heavy chain constant region fusion coding segment was clonedinto the first MCS of pEZE3. The plasmid was used to transfect CHOcells. The cells were selected in medium without hypoxanthine orthymidine and the transgene was amplified using methotrexate. Thepresence of protein was assayed by Western blotting using anti humangamma 1 heavy chain constant region and anti human kappa light chainantibodies. N-terminal sequencing revealed that the optimized tPA leaderwas not completely cleaved. The observed mass indicated that the firstresidue of the polypeptide sequence to be pyroglutamic acid, and theN-terminal sequence appears to be pyroEEIHAELRRFRRVPCVSGG (SEQ ID NO:64), the underlined portion being remnants of the tPA leader.

EXAMPLE 6 IL-20 Transgenic Phenotype

[0113] Both human and mouse IL-20 were overexpressed in transgenic miceusing a variety of promoters. The liver-specific mouse albumin promoter,directing expression of human IL-20, was used initially in an attempt toachieve circulating levels of protein. Subsequent studies were conductedusing the keratin 14 (K14) promoter, which primarily targets expressionto the epidermis and other stratified squamous epithelia; the mousemetallothionein- 1 promoter, which gives a broad expression pattern; andthe EμLCK promoter, which drives expression in cells of the lymphoidlineage. Similar results were obtained in all four cases, possiblybecause these promoters all give rise to circulating levels of L-20.

[0114] In all cases, transgenic pups expressing the L-20 transgene weresmaller than non-transgenic littermates, had a shiny appearance withtight, wrinkled skin and died within the first few days after birth.Pups had milk in their stomachs indicating that they were able tosuckle. These mice had swollen extremities, tail, nostril and mouthregions and had difficulty moving. In addition, the mice were frail,lacked visible adipose tissue and had delayed ear and toe development.Low expression levels in liver (less than 100 mRNA molecules/cell) weresufficient for both the neonatal lethality and skin abnormalities.Transgenic mice without a visible phenotype either did not express thetransgene, did not express it at detectable levels, or were mosaic.

[0115] Histologic analysis of the skin of the IL-20 transgenic miceshowed a thickened epidermis, hyperkeratosis and a compact stratumcorneum compared to non-transgenic littermates. Serocellular crusts(scabs) were observed occasionally. Electron microscopic (EM) analysisof skin from transgenic mice showed intramitochondrial lipoidinclusions, mottled keratohyaline granules, and relatively fewtonofilaments similar to that observed in human psoriatic skin and inmouse skin disease models. In addition, many of the transgenic mice hadapoptotic thymic lymphocytes. No other abnormalities were detected byhistopathological analysis. These histological and EM results supportand extend the observed gross skin alterations.

EXAMPLE 7 Specificity and Affinity of IL-20 for Its Receptor

[0116] The specificity and affinity of IL-20 for its receptor wasdetermined using BHK cells stably transfected with IL-20RA, IL-20RB orboth receptor subunits. Binding assays using radiolabeled liganddemonstrated that IL-20 bound to BHK transfectants expressing bothIL-20RA and IL-20RB but not to untransfected cells nor to transfectantsexpressing either receptor subunit alone. Binding of ¹²⁵I-labeled IL-20was eliminated in the presence of 100-fold excess of unlabeled IL-20 butnot with 100-fold excess of the unrelated cytokine, IL-21. The bindingaffinity (k_(D)) of IL-20 to the IL-20RA/IL-20RB heterodimeric receptorwas determined to be approximately 1.5 nM.

EXAMPLE 8 IL-20 receptor Activation

[0117] To determine if IL-20 binding leads to receptor activation, thefactor-dependent pre-B cell line BaF3 was co-transfected with IL-20RAand IL-20RB and treated with IL-20 at various concentrations. IL-20stimulated proliferation in a dose-dependent manner and gave adetectable signal at 1.1 pM, with a half maximal response at 3.4 pM. Wenote that the L-20 concentration for the half maximal proliferativeresponse in BaF3 cells is 1000× lower than that for half maximal bindingaffinity in BHK cells. Possible explanations for this large differenceinclude the use of different cell lines, different receptor expressionlevels and different assay outputs. L-20 also stimulated signaltransduction in the biologically relevant human keratinocyte cell lineHaCaT, which naturally expresses IL-20RA and IL-20RB. Therefore, IL-20binds and activates the heterodimeric IL-20RA/IL-20RB receptor atconcentrations expected for a cytokine. While the negative controlscontaining untransfected BaF3

EXAMPLE 9 Expression Analysis of IL-20RA and IL-20RB

[0118] RT-PCR analysis was performed on a variety of human tissues todetermine the expression pattern of IL-20RA and IL-20RB. Both receptorsubunits are most highly expressed in skin and testis. The significantresult is that IL-20RA and IL-20RB are both expressed in skin, wherethey have been shown to mediate the IL-20-induced response. Both IL-20RAand IL-20RB are also both expressed in monocytes, lung, ovary, muscle,testis, adrenal gland, heart, salivary gland and placenta. IL-20RA isalso in brain, kidney, liver, colon, small intestine, stomach, thyroid,pancreas, uterus and prostate while IL-20RB is not.

EXAMPLE 10 IL-20RA and IL-20RB mRNA are Up-regulated in Psoriasis

[0119] In situ hybridization was used to determine whether IL-20receptor expression is altered in psoriasis. Skin samples from fourpsoriasis patients and three unaffected patients were assayed withprobes specific for the two-receptor subunit mRNAs. All four psoriaticskin samples had high levels of L-20RA and IL-20RB mRNA in keratinocyteswhereas normal skin samples did not have detectable levels of eitherreceptor subunit mRNA. Positive signals in psoriatic skin were alsoobserved in mononuclear immune cells and in endothelial cells in asubset of vessels. Therefore, both L-20RA and L-20RB are expressed inkeratinocytes, immune cells and endothelial cells, the major cell typesthought to interact in psoriasis.

EXAMPLE 11 Cloning of Mouse IL-20RA

[0120] A cross-species hybridization probe was generated which containedthe full-length cDNA fragment encoding human IL-20RA. A Southern blot ofmouse genomic DNA and Northern blots of mouse RNA were performed todemonstrate that the human IL-20RA cDNA could specifically hybridize tomouse sequences. The Northern blot results indicated that mouse IL-20RARNA was present in mouse embryo day 15 and 17 as well as heart, brain,lung, liver, kidney, testes, spleen, thymus, liver, stomach, and smallintestine.

[0121] The human IL-20RA full length DNA hybridization probe was used toscreen a mouse genomic library. The library, which was obtained fromClontech (Palo Alto, Calif.), was generated from an MboI partial digestof mouse genomic DNA and cloned into the BamHI site of Lambdabacteriophage EMBL3 SP6/T7. Positive bacteriophage was plaque purifiedand bacteriophage DNA was prepared using Promega's Wizard Lambda PrepsDNA Purification System. Two genomic restriction enzyme fragments, a 5.7kb EcoRI fragment and an 8.0 kb SacI fragment, were generated from thepositive bacteriophage and subcloned into pBluescript. DNA sequenceanalysis revealed the presence of 3 exons from the mouse ortholog tohuman IL-20RA.

[0122] PCR primers from the 5′ UTR, SEQ ID No.: 40, and 3′ UTR, SEQ IDNo.: 41, were designed to generate a full-length mouse IL-20RA sequenceby PCR amplification. Mouse embryo 15day plus 17 day cDNA was used asthe template for the PCR amplification. PCR products were subcloned andsequenced for confirmation. The mouse sequences are SEQ ID Nos.: 36 and37. The mature extracellular domain is comprised of SEQ ID No.: 38.

EXAMPLE 12 Construction of an IL-20 Receptor Heterotetramer

[0123] A vector expressing a secreted hIL-20RA/hIL-20B heterodimer wasconstructed. In this construct, the extracellular domain of hIL-20RA wasfused to the heavy chain of IgG gamma 1 (IgGγ1), while the extracellularportion of IL-20RB was fused to human kappa light chain (human κlightchain).

[0124] Construction of IgG gamma 1 and human κ light fusion vectors

[0125] The heavy chain of IgGγ1 was cloned into the Zem229R mammalianexpression vector (ATCC deposit No. 69447) such that any extracellularportion of a receptor having a 5′ EcoRI and 3′ NheI site can be clonedin, resulting in an N-terminal extracellular domain-C-terminal IgGγ1fusion. The IgGγ1 fragment used in this construct was made by using PCRto isolate the IgGγ1 sequence from a Clontech human fetal liver cDNAlibrary as template. A PCR reaction using oligos SEQ ID No.: 42 and SEQID No.: 43 was run as follows: 40 cycles of 94° for 60 sec., 53° C. for60 sec., and 72° for 120 sec.; and 72° C. for 7 minutes. PCR productswere separated by agarose gel electrophoresis and purified using aQiaQuick™ (Qiagen Inc., Valencia, Calif.) gel extraction kit. Theisolated, 990 bp, DNA fragment was digested with MluI and EcoRi(Boerhinger-Mannheim), extracted with QiaQuickTm gel extraction kit andligated with oligos SEQ ID No.: 44 and SEQ ID No.: 45, which comprise anMluI/EcoRI linker, into Zem229R previously digested with MluI and EcoRIusing standard molecular biology techniques disclosed herein. Thisgeneric cloning vector was called Vector#76 hIgGgammal w/ Ch1 #786Zem229R (Vector #76). The polynucleotide sequence of the extracellulardomain of hIL-20RA fused to the heavy chain of IgG gamma 1 is show inSEQ ID No.: 52 and the corresponding polypeptide sequence shown in SEQID No.: 53, the mature polypeptide, minus the signal sequence beingcomprised of SEQ ID No.: 54. The portion of the extracellular domain ofIL-20RA used was comprised of SEQ ID No.: 55.

[0126] The human κ light chain was cloned in the Zem228R mammalianexpression vector (ATCC deposit No. 69446) such that any extracellularportion of a receptor having a 5′ EcoRI site and a 3′ KpnI site can becloned in, resulting in an N-terminal extracellular domain-C-terminalhuman κ light chain fusion. The human κ light chain fragment used inthis construct was made by using PCR to isolate the human κ light chainsequence from the same Clontech hFetal Liver cDNA library used above. APCR reaction was run using oligos SEQ ID No.: 46 and SEQ ID No.: 47. PCRproducts were separated by agarose gel electrophoresis and purifiedusing a QiaQuick™ (Qiagen) gel extraction kit. The isolated, 315 bp, DNAfragment was digested with MluI and EcoRI (Boerhinger-Mannheim),extracted with QiaQuick™ gel extraction kit and ligated with theMluI/EcoRI linker described above, into Zem228R previously digested withMluI and EcoRI using standard molecular biology techniques disclosedherein. This generic cloning vector was called Vector #77 hκlight #774Zem228R (Vector #77). The polynucleotide sequence of the extracellularportion of IL-20RB fused to human kappa light chain is shown in SEQ IDNo.: 56 and the corresponding polypeptide sequence shown in SEQ ID No.:57, the mature polypeptide, minus the signal sequence, is comprised ofSEQ ID No.: 58. The portion of the extracellular domain of IL-20RBactually used was comprised of SEQ ID No.: 59.

[0127] Insertion of hIL-20RA and IL-20RB extracellular domains intofusion vector constructs

[0128] Using the construction vectors above, a construct having humanIL-20RA fused to IgGγ1 was made. This construction was done by using PCRto obtain human IL-20RA receptor from hIL-20RA/IgG Vector #102 witholigos SEQ ID No.: 48 and SEQ ID No.: 49 under conditions described asfollows: 30 cycles of 94° C. for 60 sec., 57° C. for 60 sec., and 72° C.for 120 sec.; and 72° C. for 7 min. The resulting PCR product wasdigested with EcoRI and NheI, gel purified, as described herein, andligated into a previously EcoRI and NheI digested and band-purifiedVector #76 (above). The resulting vector was sequenced to confirm thatthe human IL-20Rα/IgG gamma 1 fusion (hIL-20RA/Ch1 IgG) was correct. ThehIL-20RA/Ch1 IgG gamma 1 #1825 Zem229R vector was called vector #195.The IL-20RA/Ch1 IgGγ1 sequence thus obtained is depicted by SEQ ID Nos.:52 and 53. N-terminal sequencing indicated the presence of the predictedmature polypeptide sequence of SEQ ID No.: 54.

[0129] A separate construct having IL-20RB fused to κ light was alsoconstructed. The IL-20RB/human κ light chain construction was performedas above PCRing from DR1/7N-4 with oligos SEQ ID No.: 50 and SEQ ID No.:51, digesting the resulting band with EcoRI and KpnI and then ligatingthis product into a previously EcoRI and KpnI digested and band-purifiedVec#77 (above). The resulting vector was sequenced to confirm that theIL-20RB/ human κ light chain fusion (IL-20RB/κlight) was correct. ThisIL-20RB//κlight construct is shown by SEQ ID Nos.: 56 and 57. N-terminalsequencing of the resultant polypeptide indicated the presence of thepredicted mature amino acid sequence comprised of SEQ ID No.: 58. SEQ IDNo.:59 is the mature portion of the extracellular domain of IL-20RBused.

[0130] Co-expression of the human IL-20RA and human IL-20RB receptors

[0131] Approximately 16 μg of each of vectors #194 and #195, above, wereco-transfected into BHK-570 cells (ATCC No. CRL-10314) usingLipofectamine™ reagent (Gibco/BRL), as per manufacturer's instructions.The transfected cells were selected for 10 days in DMEM+5%FBS(Gibco/BRL) containing 1 μM of methotrexate (MTX) (Sigma, St. Louis,Mo.) and 0.5 mg/ml G418 (Gibco/BRL) for 10 days. The resulting pool oftransfectants was selected again in 10μM MTX and 0.5mg/ml G418 for 10days.

[0132] The resulting pool of doubly selected cells was used to generateprotein. Three factories (Nunc, Denmark) of this pool were used togenerate 8 L of serum free conditioned medium. This conditioned mediawas passed over a 1 ml protein-A column and eluted in (10) 750microliter fractions. 4 of these fractions found to have the highestconcentration were pooled and dialyzed (10 kD MW cutoff) against PBS.Finally, the dialyzed material was analyzed by BCA (Pierce) and found tohave a concentration of 317 μg/ml. A total of 951 μg was obtained fromthis 8 L purification.

EXAMPLE 13 IL-20 Binding Activates STAT3 in the HaCaT Keratinocyte CellLine

[0133] IL-20 binds cell lines transfected with both subunits of itsreceptor. However, these cell lines overexpress the IL-20 receptorrelative to its normal level and their relevance to the physiologicalrole of IL-20 is unclear. The human HaCaT keratinocyte cell line, whichexpresses endogenous IL-20RA and IL-20RB was used to examine IL-20signal transduction in a biologically relevant cell type. HaCaT cellswere infected with recombinant adenovirus containing a reporterconstruct to allow detection of intracellular signaling. The constructconsists of the firefly luciferase gene driven by promoter/enhancersequences comprised of the serum response element (SRE) and signaltransducers and activators of transduction elements (STATs). This assaysystem detects productive ligand-receptor interactions and indicatespossible downstream signal transduction components involved in receptoractivation. Treatment with IL-20 alone resulted in a dose-dependentincrease in luciferase activity with a half maximal response occurringat approximately 2.3 nM. Subsequent luciferase reporter assays usingadenovirus vectors containing only the SRE element or only the STATelements produced detectable reporter activation only through STATs.

[0134] To determine if other cytokines act in concert with IL-20, HaCaTcells were treated with IL-20 alone or in combination with a singlesubmaximal dose of EGF, IL-1β, or TNFα. In the presence of each of thesethree proteins, IL-20 treatment resulted in a dose-dependent increase inluciferase activity. IL-20 in combination with IL-1β results in ahalf-maximal response at approximately 0.5 nM, about five-fold lowerthan with IL-20 alone. In addition, activation of the reporter gene isdetectable at 0.1 nM IL-20, a dose that is at least tenfold lower thanthe IL-20 dose required alone.

[0135] BHK cells transfected with IL-20RA, IL-20RB or both receptorsubunits were used to determine whether receptor pairing was requiredfor IL-20 stimulation of STAT-luciferase. As was the case with bindingassays, only cells transfected with both receptor subunits responded toIL-20 and did so with a half-maximal response of 5.7 pM. We note thatthe IL-20 concentration for the half-maximal response in BHK cells is400-fold lower than that for half-maximal response in HaCaT cells. It islikely that a lower concentration of IL-20 is needed for half-maximalresponse in BHK cells, as compared to HaCaT cells, due to higherreceptor levels in the BHK IL-20 receptor transfectants.

[0136] A nuclear translocation assay was used to identify STAT proteinsinvolved in IL-20 action. Both HaCaT cells, with endogenous IL-20receptors, and BHK cells transfected with IL-20RA and IL-20RB, weretreated with IL-20 protein and translocation of STAT3 and STAT1transcription factors from the cytoplasm to the nucleus was assayed byimmunofluorescence.

[0137] In unstimulated HaCaT cells, STAT3 staining was predominantly inthe cytosol. Treatment of HaCaT cells with IL-20 resulted in a distinctaccumulation of STAT3 in the nucleus. Nuclear translocation of STAT3 inresponse to increasing concentrations of IL-20 occurred with ahalf-maximal IL-20 concentration of 7 nM. In contrast to STAT3translocation, HaCaT cells treated with IL-20 did not show anydetectable nuclear accumulation of STAT1.

[0138] BHK cells transfected with IL-20RA and IL-20RB were used toconfirm that the IL-20 receptor was required for IL-20 stimulation ofSTAT3 nuclear translocation. In BHK cells lacking the L-20 receptor,STAT3 remained cytosolic following treatment with IL-20. In contrast, inBHK cells transfected with the IL-20 receptor, STAT3 translocated to thenucleus in response to IL-20. Again, STAT1 remained cytosolic regardlessof IL-20 treatment or IL-20 receptor expression. We conclude that theL-20 receptor is required for IL-20-mediated STAT3 activation.

1 72 1 176 PRT Homo sapiens 1 Met Lys Ala Ser Ser Leu Ala Phe Ser LeuLeu Ser Ala Ala Phe Tyr 1 5 10 15 Leu Leu Trp Thr Pro Ser Thr Gly LeuLys Thr Leu Asn Leu Gly Ser 20 25 30 Cys Val Ile Ala Thr Asn Leu Gln GluIle Arg Asn Gly Phe Ser Asp 35 40 45 Ile Arg Gly Ser Val Gln Ala Lys AspGly Asn Ile Asp Ile Arg Ile 50 55 60 Leu Arg Arg Thr Glu Ser Leu Gln AspThr Lys Pro Ala Asn Arg Cys 65 70 75 80 Cys Leu Leu Arg His Leu Leu ArgLeu Tyr Leu Asp Arg Val Phe Lys 85 90 95 Asn Tyr Gln Thr Pro Asp His TyrThr Leu Arg Lys Ile Ser Ser Leu 100 105 110 Ala Asn Ser Phe Leu Thr IleLys Lys Asp Leu Arg Leu Cys His Ala 115 120 125 His Met Thr Cys His CysGly Glu Glu Ala Met Lys Lys Tyr Ser Gln 130 135 140 Ile Leu Ser His PheGlu Lys Leu Glu Pro Gln Ala Ala Val Val Lys 145 150 155 160 Ala Leu GlyGlu Leu Asp Ile Leu Leu Gln Trp Met Glu Glu Thr Glu 165 170 175 2 152PRT Homo sapiens 2 Leu Lys Thr Leu Asn Leu Gly Ser Cys Val Ile Ala ThrAsn Leu Gln 1 5 10 15 Glu Ile Arg Asn Gly Phe Ser Asp Ile Arg Gly SerVal Gln Ala Lys 20 25 30 Asp Gly Asn Ile Asp Ile Arg Ile Leu Arg Arg ThrGlu Ser Leu Gln 35 40 45 Asp Thr Lys Pro Ala Asn Arg Cys Cys Leu Leu ArgHis Leu Leu Arg 50 55 60 Leu Tyr Leu Asp Arg Val Phe Lys Asn Tyr Gln ThrPro Asp His Tyr 65 70 75 80 Thr Leu Arg Lys Ile Ser Ser Leu Ala Asn SerPhe Leu Thr Ile Lys 85 90 95 Lys Asp Leu Arg Leu Cys His Ala His Met ThrCys His Cys Gly Glu 100 105 110 Glu Ala Met Lys Lys Tyr Ser Gln Ile LeuSer His Phe Glu Lys Leu 115 120 125 Glu Pro Gln Ala Ala Val Val Lys AlaLeu Gly Glu Leu Asp Ile Leu 130 135 140 Leu Gln Trp Met Glu Glu Thr Glu145 150 3 151 PRT Homo sapiens 3 Met Lys Ala Ser Ser Leu Ala Phe Ser LeuLeu Ser Ala Ala Phe Tyr 1 5 10 15 Leu Leu Trp Thr Pro Ser Thr Gly LeuLys Thr Leu Asn Leu Gly Ser 20 25 30 Cys Val Ile Ala Thr Asn Leu Gln GluIle Arg Asn Gly Phe Ser Asp 35 40 45 Ile Arg Gly Ser Val Gln Ala Lys AspGly Asn Ile Asp Ile Arg Ile 50 55 60 Leu Arg Arg Thr Glu Ser Leu Gln AspThr Lys Pro Ala Asn Arg Cys 65 70 75 80 Cys Leu Leu Arg His Leu Leu ArgLeu Tyr Leu Asp Arg Val Phe Lys 85 90 95 Asn Tyr Gln Thr Pro Asp His TyrThr Leu Arg Lys Ile Ser Ser Leu 100 105 110 Ala Asn Ser Phe Leu Thr IleLys Lys Asp Leu Arg Leu Cys Leu Glu 115 120 125 Pro Gln Ala Ala Val ValLys Ala Leu Gly Glu Leu Asp Ile Leu Leu 130 135 140 Gln Trp Met Glu GluThr Glu 145 150 4 127 PRT Homo sapiens 4 Leu Lys Thr Leu Asn Leu Gly SerCys Val Ile Ala Thr Asn Leu Gln 1 5 10 15 Glu Ile Arg Asn Gly Phe SerAsp Ile Arg Gly Ser Val Gln Ala Lys 20 25 30 Asp Gly Asn Ile Asp Ile ArgIle Leu Arg Arg Thr Glu Ser Leu Gln 35 40 45 Asp Thr Lys Pro Ala Asn ArgCys Cys Leu Leu Arg His Leu Leu Arg 50 55 60 Leu Tyr Leu Asp Arg Val PheLys Asn Tyr Gln Thr Pro Asp His Tyr 65 70 75 80 Thr Leu Arg Lys Ile SerSer Leu Ala Asn Ser Phe Leu Thr Ile Lys 85 90 95 Lys Asp Leu Arg Leu CysLeu Glu Pro Gln Ala Ala Val Val Lys Ala 100 105 110 Leu Gly Glu Leu AspIle Leu Leu Gln Trp Met Glu Glu Thr Glu 115 120 125 5 176 PRT Musmusculis 5 Met Lys Gly Phe Gly Leu Ala Phe Gly Leu Phe Ser Ala Val GlyPhe 1 5 10 15 Leu Leu Trp Thr Pro Leu Thr Gly Leu Lys Thr Leu His LeuGly Ser 20 25 30 Cys Val Ile Thr Ala Asn Leu Gln Ala Ile Gln Lys Glu PheSer Glu 35 40 45 Ile Arg Asp Ser Val Gln Ala Glu Asp Thr Asn Ile Asp IleArg Ile 50 55 60 Leu Arg Thr Thr Glu Ser Leu Lys Asp Ile Lys Ser Leu AspArg Cys 65 70 75 80 Cys Phe Leu Arg His Leu Val Arg Phe Tyr Leu Asp ArgVal Phe Lys 85 90 95 Val Tyr Gln Thr Pro Asp His His Thr Leu Arg Lys IleSer Ser Leu 100 105 110 Ala Asn Ser Phe Leu Ile Ile Lys Lys Asp Leu SerVal Cys His Ser 115 120 125 His Met Ala Cys His Cys Gly Glu Glu Ala MetGlu Lys Tyr Asn Gln 130 135 140 Ile Leu Ser His Phe Ile Glu Leu Glu LeuGln Ala Ala Val Val Lys 145 150 155 160 Ala Leu Gly Glu Leu Gly Ile LeuLeu Arg Trp Met Glu Glu Met Leu 165 170 175 6 152 PRT Mus musculis 6 LeuLys Thr Leu His Leu Gly Ser Cys Val Ile Thr Ala Asn Leu Gln 1 5 10 15Ala Ile Gln Lys Glu Phe Ser Glu Ile Arg Asp Ser Val Gln Ala Glu 20 25 30Asp Thr Asn Ile Asp Ile Arg Ile Leu Arg Thr Thr Glu Ser Leu Lys 35 40 45Asp Ile Lys Ser Leu Asp Arg Cys Cys Phe Leu Arg His Leu Val Arg 50 55 60Phe Tyr Leu Asp Arg Val Phe Lys Val Tyr Gln Thr Pro Asp His His 65 70 7580 Thr Leu Arg Lys Ile Ser Ser Leu Ala Asn Ser Phe Leu Ile Ile Lys 85 9095 Lys Asp Leu Ser Val Cys His Ser His Met Ala Cys His Cys Gly Glu 100105 110 Glu Ala Met Glu Lys Tyr Asn Gln Ile Leu Ser His Phe Ile Glu Leu115 120 125 Glu Leu Gln Ala Ala Val Val Lys Ala Leu Gly Glu Leu Gly IleLeu 130 135 140 Leu Arg Trp Met Glu Glu Met Leu 145 150 7 144 PRT Musmusculis 7 Cys Val Ile Thr Ala Asn Leu Gln Ala Ile Gln Lys Glu Phe SerGlu 1 5 10 15 Ile Arg Asp Ser Val Gln Ala Glu Asp Thr Asn Ile Asp IleArg Ile 20 25 30 Leu Arg Thr Thr Glu Ser Leu Lys Asp Ile Lys Ser Leu AspArg Cys 35 40 45 Cys Phe Leu Arg His Leu Val Arg Phe Tyr Leu Asp Arg ValPhe Lys 50 55 60 Val Tyr Gln Thr Pro Asp His His Thr Leu Arg Lys Ile SerSer Leu 65 70 75 80 Ala Asn Ser Phe Leu Ile Ile Lys Lys Asp Leu Ser ValCys His Ser 85 90 95 His Met Ala Cys His Cys Gly Glu Glu Ala Met Glu LysTyr Asn Gln 100 105 110 Ile Leu Ser His Phe Ile Glu Leu Glu Leu Gln AlaAla Val Val Lys 115 120 125 Ala Leu Gly Glu Leu Gly Ile Leu Leu Arg TrpMet Glu Glu Met Leu 130 135 140 8 154 PRT Mus musculis 8 Met Lys Gly PheGly Leu Ala Phe Gly Leu Phe Ser Ala Val Gly Phe 1 5 10 15 Leu Leu TrpThr Pro Leu Thr Gly Leu Lys Thr Leu His Leu Gly Ser 20 25 30 Cys Val IleThr Ala Asn Leu Gln Ala Ile Gln Lys Glu Phe Ser Glu 35 40 45 Ile Arg AspSer Val Ser Leu Asp Arg Cys Cys Phe Leu Arg His Leu 50 55 60 Val Arg PheTyr Leu Asp Arg Val Phe Lys Val Tyr Gln Thr Pro Asp 65 70 75 80 His HisThr Leu Arg Lys Ile Ser Ser Leu Ala Asn Ser Phe Leu Ile 85 90 95 Ile LysLys Asp Leu Ser Val Cys His Ser His Met Ala Cys His Cys 100 105 110 GlyGlu Glu Ala Met Glu Lys Tyr Asn Gln Ile Leu Ser His Phe Ile 115 120 125Glu Leu Glu Leu Gln Ala Ala Val Val Lys Ala Leu Gly Glu Leu Gly 130 135140 Ile Leu Leu Arg Trp Met Glu Glu Met Leu 145 150 9 130 PRT Homosapiens 9 Leu Lys Thr Leu His Leu Gly Ser Cys Val Ile Thr Ala Asn LeuGln 1 5 10 15 Ala Ile Gln Lys Glu Phe Ser Glu Ile Arg Asp Ser Val SerLeu Asp 20 25 30 Arg Cys Cys Phe Leu Arg His Leu Val Arg Phe Tyr Leu AspArg Val 35 40 45 Phe Lys Val Tyr Gln Thr Pro Asp His His Thr Leu Arg LysIle Ser 50 55 60 Ser Leu Ala Asn Ser Phe Leu Ile Ile Lys Lys Asp Leu SerVal Cys 65 70 75 80 His Ser His Met Ala Cys His Cys Gly Glu Glu Ala MetGlu Lys Tyr 85 90 95 Asn Gln Ile Leu Ser His Phe Ile Glu Leu Glu Leu GlnAla Ala Val 100 105 110 Val Lys Ala Leu Gly Glu Leu Gly Ile Leu Leu ArgTrp Met Glu Glu 115 120 125 Met Leu 130 10 3516 DNA Homo sapiens CDS(237)...(1895) 10 tccagctggg tagccggggg agcgcgcgtg ggggctccgc gagtcgctcgcccttggttt 60 ctggggaagc ctgggggacg cggctgtggc ggaggcgccc tgggactcaggtcgcctgga 120 gcgtggcacg cagagcccca ggcgcggagc tgaggccgcg cggccgcgcttggccccagc 180 gggcgtggga ctgagcagtc tgctgccccc cgacatgtga cccagccccgccgccc atg 239 Met 1 cgg gct ccc ggc cgc ccg gcc ctg cgg ccg ctg ccg ctgccg ccg ctg 287 Arg Ala Pro Gly Arg Pro Ala Leu Arg Pro Leu Pro Leu ProPro Leu 5 10 15 ctg ctg ttg ctc ctg gcg gcg cct tgg gga cgg gca gtt ccctgt gtc 335 Leu Leu Leu Leu Leu Ala Ala Pro Trp Gly Arg Ala Val Pro CysVal 20 25 30 tct ggt ggt ttg cct aaa cct gca aac atc acc ttc tta tcc atcaac 383 Ser Gly Gly Leu Pro Lys Pro Ala Asn Ile Thr Phe Leu Ser Ile Asn35 40 45 atg aag aat gtc cta caa tgg act cca cca gag ggt ctt caa gga gtt431 Met Lys Asn Val Leu Gln Trp Thr Pro Pro Glu Gly Leu Gln Gly Val 5055 60 65 aaa gtt act tac act gtg cag tat ttc ata tat ggg caa aag aaa tgg479 Lys Val Thr Tyr Thr Val Gln Tyr Phe Ile Tyr Gly Gln Lys Lys Trp 7075 80 ctg aat aaa tca gaa tgc aga aat atc aat aga acc tac tgt gat ctt527 Leu Asn Lys Ser Glu Cys Arg Asn Ile Asn Arg Thr Tyr Cys Asp Leu 8590 95 tct gct gaa act tct gac tac gaa cac cag tat tat gcc aaa gtt aag575 Ser Ala Glu Thr Ser Asp Tyr Glu His Gln Tyr Tyr Ala Lys Val Lys 100105 110 gcc att tgg gga aca aag tgt tcc aaa tgg gct gaa agt gga cgg ttc623 Ala Ile Trp Gly Thr Lys Cys Ser Lys Trp Ala Glu Ser Gly Arg Phe 115120 125 tat cct ttt tta gaa aca caa att ggc cca cca gag gtg gca ctg act671 Tyr Pro Phe Leu Glu Thr Gln Ile Gly Pro Pro Glu Val Ala Leu Thr 130135 140 145 aca gat gag aag tcc att tct gtt gtc ctg aca gct cca gag aagtgg 719 Thr Asp Glu Lys Ser Ile Ser Val Val Leu Thr Ala Pro Glu Lys Trp150 155 160 aag aga aat cca gaa gac ctt cct gtt tcc atg caa caa ata tactcc 767 Lys Arg Asn Pro Glu Asp Leu Pro Val Ser Met Gln Gln Ile Tyr Ser165 170 175 aat ctg aag tat aac gtg tct gtg ttg aat act aaa tca aac agaacg 815 Asn Leu Lys Tyr Asn Val Ser Val Leu Asn Thr Lys Ser Asn Arg Thr180 185 190 tgg tcc cag tgt gtg acc aac cac acg ctg gtg ctc acc tgg ctggag 863 Trp Ser Gln Cys Val Thr Asn His Thr Leu Val Leu Thr Trp Leu Glu195 200 205 ccg aac act ctt tac tgc gta cac gtg gag tcc ttc gtc cca gggccc 911 Pro Asn Thr Leu Tyr Cys Val His Val Glu Ser Phe Val Pro Gly Pro210 215 220 225 cct cgc cgt gct cag cct tct gag aag cag tgt gcc agg actttg aaa 959 Pro Arg Arg Ala Gln Pro Ser Glu Lys Gln Cys Ala Arg Thr LeuLys 230 235 240 gat caa tca tca gag ttc aag gct aaa atc atc ttc tgg tatgtt ttg 1007 Asp Gln Ser Ser Glu Phe Lys Ala Lys Ile Ile Phe Trp Tyr ValLeu 245 250 255 ccc ata tct att acc gtg ttt ctt ttt tct gtg atg ggc tattcc atc 1055 Pro Ile Ser Ile Thr Val Phe Leu Phe Ser Val Met Gly Tyr SerIle 260 265 270 tac cga tat atc cac gtt ggc aaa gag aaa cac cca gca aatttg att 1103 Tyr Arg Tyr Ile His Val Gly Lys Glu Lys His Pro Ala Asn LeuIle 275 280 285 ttg att tat gga aat gaa ttt gac aaa aga ttc ttt gtg cctgct gaa 1151 Leu Ile Tyr Gly Asn Glu Phe Asp Lys Arg Phe Phe Val Pro AlaGlu 290 295 300 305 aaa atc gtg att aac ttt atc acc ctc aat atc tcg gatgat tct aaa 1199 Lys Ile Val Ile Asn Phe Ile Thr Leu Asn Ile Ser Asp AspSer Lys 310 315 320 att tct cat cag gat atg agt tta ctg gga aaa agc agtgat gta tcc 1247 Ile Ser His Gln Asp Met Ser Leu Leu Gly Lys Ser Ser AspVal Ser 325 330 335 agc ctt aat gat cct cag ccc agc ggg aac ctg agg ccccct cag gag 1295 Ser Leu Asn Asp Pro Gln Pro Ser Gly Asn Leu Arg Pro ProGln Glu 340 345 350 gaa gag gag gtg aaa cat tta ggg tat gct tcg cat ttgatg gaa att 1343 Glu Glu Glu Val Lys His Leu Gly Tyr Ala Ser His Leu MetGlu Ile 355 360 365 ttt tgt gac tct gaa gaa aac acg gaa ggt act tct ttcacc cag caa 1391 Phe Cys Asp Ser Glu Glu Asn Thr Glu Gly Thr Ser Phe ThrGln Gln 370 375 380 385 gag tcc ctc agc aga aca ata ccc ccg gat aaa acagtc att gaa tat 1439 Glu Ser Leu Ser Arg Thr Ile Pro Pro Asp Lys Thr ValIle Glu Tyr 390 395 400 gaa tat gat gtc aga acc act gac att tgt gcg gggcct gaa gag cag 1487 Glu Tyr Asp Val Arg Thr Thr Asp Ile Cys Ala Gly ProGlu Glu Gln 405 410 415 gag ctc agt ttg cag gag gag gtg tcc aca caa ggaaca tta ttg gag 1535 Glu Leu Ser Leu Gln Glu Glu Val Ser Thr Gln Gly ThrLeu Leu Glu 420 425 430 tcg cag gca gcg ttg gca gtc ttg ggc ccg caa acgtta cag tac tca 1583 Ser Gln Ala Ala Leu Ala Val Leu Gly Pro Gln Thr LeuGln Tyr Ser 435 440 445 tac acc cct cag ctc caa gac tta gac ccc ctg gcgcag gag cac aca 1631 Tyr Thr Pro Gln Leu Gln Asp Leu Asp Pro Leu Ala GlnGlu His Thr 450 455 460 465 gac tcg gag gag ggg ccg gag gaa gag cca tcgacg acc ctg gtc gac 1679 Asp Ser Glu Glu Gly Pro Glu Glu Glu Pro Ser ThrThr Leu Val Asp 470 475 480 tgg gat ccc caa act ggc agg ctg tgt att ccttcg ctg tcc agc ttc 1727 Trp Asp Pro Gln Thr Gly Arg Leu Cys Ile Pro SerLeu Ser Ser Phe 485 490 495 gac cag gat tca gag ggc tgc gag cct tct gagggg gat ggg ctc gga 1775 Asp Gln Asp Ser Glu Gly Cys Glu Pro Ser Glu GlyAsp Gly Leu Gly 500 505 510 gag gag ggt ctt cta tct aga ctc tat gag gagccg gct cca gac agg 1823 Glu Glu Gly Leu Leu Ser Arg Leu Tyr Glu Glu ProAla Pro Asp Arg 515 520 525 cca cca gga gaa aat gaa acc tat ctc atg caattc atg gag gaa tgg 1871 Pro Pro Gly Glu Asn Glu Thr Tyr Leu Met Gln PheMet Glu Glu Trp 530 535 540 545 ggg tta tat gtg cag atg gaa aactgatgccaac acttcctttt gccttttgtt 1925 Gly Leu Tyr Val Gln Met Glu Asn550 tcctgtgcaa acaagtgagt cacccctttg atcccagcca taaagtacct gggatgaaag1985 aagttttttc cagtttgtca gtgtctgtga gaattactta tttcttttct ctattctcat2045 agcacgtgtg tgattggttc atgcatgtag gtctcttaac aatgatggtg ggcctctgga2105 gtccaggggc tggccggttg ttctatgcag agaaagcagt caataaatgt ttgccagact2165 gggtgcagaa tttattcagg tgggtgtact ctggcctctt ggttcattat tttcaaacaa2225 gcacacttgt acaattattt tctgggtact tcccatatgc acatagcact gtaaaaaata2285 tttcccaaag atcactcatt ttataaatac cactttttca gaattgggtt tattgcgagc2345 aggaggagat acttaaaaca tgcacatata ccaggttggt ggtaagttgg tcacatgtga2405 aaacctcaac tatttaatca tcatgattca tattttgagt gaatacatca ggcacagacc2465 ttcatgatat cacacactct tggctacttt aagaggccat ctttaatact ttatgagtag2525 ttctggagtg taaacataaa cgagtattct tttgtagtca gaaaagtgtc ctctcaataa2585 tttagtaggg gcttattgtc tctcaaaact aacctaaaag aaaatgacac attttataat2645 agaatattac atttatttct ggaagtgtgt tttcaaaaag atatttacat agtctgtaaa2705 ctagaaagtg ttaggtaaag ctctaggtta ctgtgttact attataatat taaacattcg2765 aataggcagt cgttcaaaga ctctttggaa tatctatgaa tgaatatcct ctattcttat2825 aatattaaaa cccataagta aatataggac atacaagaga aatgagttaa atgactatgt2885 aagggagagt ttattaaaat ttgatgaaat ttactgtagg aactaaacta tgccataaaa2945 caatagcttt ctagttcatt tccagtaact gttcccatct cctttaccac ttgttaagaa3005 aattaaattc ttcagtcacg ctgctttaaa atgggacaaa atctattaag ttgaaccata3065 tataattgtg gatatttggc tgtttttaat ctgacaagca gtaacttcat atggtttgcc3125 ttaatatata tttgttttag tcatgaactc ataatccatt gatgctcttt catgagaaga3185 gatatgaccc atatttcctt attgatatta ttggtacagg cagacaaccc tggtaggaga3245 gatggattct ggggtcatga cctttcgtga ttatccgcaa atgcaaacag tttcagatct3305 aatggtttaa tttagggagt aattatatta atcagagtgt tctgttattc tcaatcttta3365 tagaaacgat tctgctggtt ttgaagaaca gatgtattac actaactgta aaagtagttc3425 aagagtgaga aagaataaat tgttattaag agcaaaagaa aaataaagtg attgatgata3485 aaaaaaaaaa aaaaaaagcg gccgcctcga g 3516 11 553 PRT Homo sapiens 11Met Arg Ala Pro Gly Arg Pro Ala Leu Arg Pro Leu Pro Leu Pro Pro 1 5 1015 Leu Leu Leu Leu Leu Leu Ala Ala Pro Trp Gly Arg Ala Val Pro Cys 20 2530 Val Ser Gly Gly Leu Pro Lys Pro Ala Asn Ile Thr Phe Leu Ser Ile 35 4045 Asn Met Lys Asn Val Leu Gln Trp Thr Pro Pro Glu Gly Leu Gln Gly 50 5560 Val Lys Val Thr Tyr Thr Val Gln Tyr Phe Ile Tyr Gly Gln Lys Lys 65 7075 80 Trp Leu Asn Lys Ser Glu Cys Arg Asn Ile Asn Arg Thr Tyr Cys Asp 8590 95 Leu Ser Ala Glu Thr Ser Asp Tyr Glu His Gln Tyr Tyr Ala Lys Val100 105 110 Lys Ala Ile Trp Gly Thr Lys Cys Ser Lys Trp Ala Glu Ser GlyArg 115 120 125 Phe Tyr Pro Phe Leu Glu Thr Gln Ile Gly Pro Pro Glu ValAla Leu 130 135 140 Thr Thr Asp Glu Lys Ser Ile Ser Val Val Leu Thr AlaPro Glu Lys 145 150 155 160 Trp Lys Arg Asn Pro Glu Asp Leu Pro Val SerMet Gln Gln Ile Tyr 165 170 175 Ser Asn Leu Lys Tyr Asn Val Ser Val LeuAsn Thr Lys Ser Asn Arg 180 185 190 Thr Trp Ser Gln Cys Val Thr Asn HisThr Leu Val Leu Thr Trp Leu 195 200 205 Glu Pro Asn Thr Leu Tyr Cys ValHis Val Glu Ser Phe Val Pro Gly 210 215 220 Pro Pro Arg Arg Ala Gln ProSer Glu Lys Gln Cys Ala Arg Thr Leu 225 230 235 240 Lys Asp Gln Ser SerGlu Phe Lys Ala Lys Ile Ile Phe Trp Tyr Val 245 250 255 Leu Pro Ile SerIle Thr Val Phe Leu Phe Ser Val Met Gly Tyr Ser 260 265 270 Ile Tyr ArgTyr Ile His Val Gly Lys Glu Lys His Pro Ala Asn Leu 275 280 285 Ile LeuIle Tyr Gly Asn Glu Phe Asp Lys Arg Phe Phe Val Pro Ala 290 295 300 GluLys Ile Val Ile Asn Phe Ile Thr Leu Asn Ile Ser Asp Asp Ser 305 310 315320 Lys Ile Ser His Gln Asp Met Ser Leu Leu Gly Lys Ser Ser Asp Val 325330 335 Ser Ser Leu Asn Asp Pro Gln Pro Ser Gly Asn Leu Arg Pro Pro Gln340 345 350 Glu Glu Glu Glu Val Lys His Leu Gly Tyr Ala Ser His Leu MetGlu 355 360 365 Ile Phe Cys Asp Ser Glu Glu Asn Thr Glu Gly Thr Ser PheThr Gln 370 375 380 Gln Glu Ser Leu Ser Arg Thr Ile Pro Pro Asp Lys ThrVal Ile Glu 385 390 395 400 Tyr Glu Tyr Asp Val Arg Thr Thr Asp Ile CysAla Gly Pro Glu Glu 405 410 415 Gln Glu Leu Ser Leu Gln Glu Glu Val SerThr Gln Gly Thr Leu Leu 420 425 430 Glu Ser Gln Ala Ala Leu Ala Val LeuGly Pro Gln Thr Leu Gln Tyr 435 440 445 Ser Tyr Thr Pro Gln Leu Gln AspLeu Asp Pro Leu Ala Gln Glu His 450 455 460 Thr Asp Ser Glu Glu Gly ProGlu Glu Glu Pro Ser Thr Thr Leu Val 465 470 475 480 Asp Trp Asp Pro GlnThr Gly Arg Leu Cys Ile Pro Ser Leu Ser Ser 485 490 495 Phe Asp Gln AspSer Glu Gly Cys Glu Pro Ser Glu Gly Asp Gly Leu 500 505 510 Gly Glu GluGly Leu Leu Ser Arg Leu Tyr Glu Glu Pro Ala Pro Asp 515 520 525 Arg ProPro Gly Glu Asn Glu Thr Tyr Leu Met Gln Phe Met Glu Glu 530 535 540 TrpGly Leu Tyr Val Gln Met Glu Asn 545 550 12 221 PRT Homo sapiens 12 ValPro Cys Val Ser Gly Gly Leu Pro Lys Pro Ala Asn Ile Thr Phe 1 5 10 15Leu Ser Ile Asn Met Lys Asn Val Leu Gln Trp Thr Pro Pro Glu Gly 20 25 30Leu Gln Gly Val Lys Val Thr Tyr Thr Val Gln Tyr Phe Ile Tyr Gly 35 40 45Gln Lys Lys Trp Leu Asn Lys Ser Glu Cys Arg Asn Ile Asn Arg Thr 50 55 60Tyr Cys Asp Leu Ser Ala Glu Thr Ser Asp Tyr Glu His Gln Tyr Tyr 65 70 7580 Ala Lys Val Lys Ala Ile Trp Gly Thr Lys Cys Ser Lys Trp Ala Glu 85 9095 Ser Gly Arg Phe Tyr Pro Phe Leu Glu Thr Gln Ile Gly Pro Pro Glu 100105 110 Val Ala Leu Thr Thr Asp Glu Lys Ser Ile Ser Val Val Leu Thr Ala115 120 125 Pro Glu Lys Trp Lys Arg Asn Pro Glu Asp Leu Pro Val Ser MetGln 130 135 140 Gln Ile Tyr Ser Asn Leu Lys Tyr Asn Val Ser Val Leu AsnThr Lys 145 150 155 160 Ser Asn Arg Thr Trp Ser Gln Cys Val Thr Asn HisThr Leu Val Leu 165 170 175 Thr Trp Leu Glu Pro Asn Thr Leu Tyr Cys ValHis Val Glu Ser Phe 180 185 190 Val Pro Gly Pro Pro Arg Arg Ala Gln ProSer Glu Lys Gln Cys Ala 195 200 205 Arg Thr Leu Lys Asp Gln Ser Ser GluPhe Lys Ala Lys 210 215 220 13 971 DNA Homo sapiens CDS (18)...(950) 13gaattcgagt ctaccaa atg cag act ttc aca atg gtt cta gaa gaa atc 50 MetGln Thr Phe Thr Met Val Leu Glu Glu Ile 1 5 10 tgg aca agt ctt ttc atgtgg ttt ttc tac gca ttg att cca tgt ttg 98 Trp Thr Ser Leu Phe Met TrpPhe Phe Tyr Ala Leu Ile Pro Cys Leu 15 20 25 ctc aca gat gaa gtg gcc attctg cct gcc cct cag aac ctc tct gta 146 Leu Thr Asp Glu Val Ala Ile LeuPro Ala Pro Gln Asn Leu Ser Val 30 35 40 ctc tca acc aac atg aag cat ctcttg atg tgg agc cca gtg atc gcg 194 Leu Ser Thr Asn Met Lys His Leu LeuMet Trp Ser Pro Val Ile Ala 45 50 55 cct gga gaa aca gtg tac tat tct gtcgaa tac cag ggg gag tac gag 242 Pro Gly Glu Thr Val Tyr Tyr Ser Val GluTyr Gln Gly Glu Tyr Glu 60 65 70 75 agc ctg tac acg agc cac atc tgg atcccc agc agc tgg tgc tca ctc 290 Ser Leu Tyr Thr Ser His Ile Trp Ile ProSer Ser Trp Cys Ser Leu 80 85 90 act gaa ggt cct gag tgt gat gtc act gatgac atc acg gcc act gtg 338 Thr Glu Gly Pro Glu Cys Asp Val Thr Asp AspIle Thr Ala Thr Val 95 100 105 cca tac aac ctt cgt gtc agg gcc aca ttgggc tca cag acc tca gcc 386 Pro Tyr Asn Leu Arg Val Arg Ala Thr Leu GlySer Gln Thr Ser Ala 110 115 120 tgg agc atc ctg aag cat ccc ttt aat agaaac tca acc atc ctt acc 434 Trp Ser Ile Leu Lys His Pro Phe Asn Arg AsnSer Thr Ile Leu Thr 125 130 135 cga cct ggg atg gag atc acc aaa gat ggcttc cac ctg gtt att gag 482 Arg Pro Gly Met Glu Ile Thr Lys Asp Gly PheHis Leu Val Ile Glu 140 145 150 155 ctg gag gac ctg ggg ccc cag ttt gagttc ctt gtg gcc tac tgg agg 530 Leu Glu Asp Leu Gly Pro Gln Phe Glu PheLeu Val Ala Tyr Trp Arg 160 165 170 agg gag cct ggt gcc gag gaa cat gtcaaa atg gtg agg agt ggg ggt 578 Arg Glu Pro Gly Ala Glu Glu His Val LysMet Val Arg Ser Gly Gly 175 180 185 att cca gtg cac cta gaa acc atg gagcca ggg gct gca tac tgt gtg 626 Ile Pro Val His Leu Glu Thr Met Glu ProGly Ala Ala Tyr Cys Val 190 195 200 aag gcc cag aca ttc gtg aag gcc attggg agg tac agc gcc ttc agc 674 Lys Ala Gln Thr Phe Val Lys Ala Ile GlyArg Tyr Ser Ala Phe Ser 205 210 215 cag aca gaa tgt gtg gag gtg caa ggagag gcc att ccc ctg gta ctg 722 Gln Thr Glu Cys Val Glu Val Gln Gly GluAla Ile Pro Leu Val Leu 220 225 230 235 gcc ctg ttt gcc ttt gtt ggc ttcatg ctg atc ctt gtg gtc gtg cca 770 Ala Leu Phe Ala Phe Val Gly Phe MetLeu Ile Leu Val Val Val Pro 240 245 250 ctg ttc gtc tgg aaa atg ggc cggctg ctc cag tac tcc tgt tgc ccc 818 Leu Phe Val Trp Lys Met Gly Arg LeuLeu Gln Tyr Ser Cys Cys Pro 255 260 265 gtg gtg gtc ctc cca gac acc ttgaaa ata acc aat tca ccc cag aag 866 Val Val Val Leu Pro Asp Thr Leu LysIle Thr Asn Ser Pro Gln Lys 270 275 280 tta atc agc tgc aga agg gag gaggtg gat gcc tgt gcc acg gct gtg 914 Leu Ile Ser Cys Arg Arg Glu Glu ValAsp Ala Cys Ala Thr Ala Val 285 290 295 atg tct cct gag gaa ctc ctc agggcc tgg atc tca taggtttgcg 960 Met Ser Pro Glu Glu Leu Leu Arg Ala TrpIle Ser 300 305 310 gaaggctcga g 971 14 311 PRT Homo sapiens 14 Met GlnThr Phe Thr Met Val Leu Glu Glu Ile Trp Thr Ser Leu Phe 1 5 10 15 MetTrp Phe Phe Tyr Ala Leu Ile Pro Cys Leu Leu Thr Asp Glu Val 20 25 30 AlaIle Leu Pro Ala Pro Gln Asn Leu Ser Val Leu Ser Thr Asn Met 35 40 45 LysHis Leu Leu Met Trp Ser Pro Val Ile Ala Pro Gly Glu Thr Val 50 55 60 TyrTyr Ser Val Glu Tyr Gln Gly Glu Tyr Glu Ser Leu Tyr Thr Ser 65 70 75 80His Ile Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu Gly Pro Glu 85 90 95Cys Asp Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr Asn Leu Arg 100 105110 Val Arg Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser Ile Leu Lys 115120 125 His Pro Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro Gly Met Glu130 135 140 Ile Thr Lys Asp Gly Phe His Leu Val Ile Glu Leu Glu Asp LeuGly 145 150 155 160 Pro Gln Phe Glu Phe Leu Val Ala Tyr Trp Arg Arg GluPro Gly Ala 165 170 175 Glu Glu His Val Lys Met Val Arg Ser Gly Gly IlePro Val His Leu 180 185 190 Glu Thr Met Glu Pro Gly Ala Ala Tyr Cys ValLys Ala Gln Thr Phe 195 200 205 Val Lys Ala Ile Gly Arg Tyr Ser Ala PheSer Gln Thr Glu Cys Val 210 215 220 Glu Val Gln Gly Glu Ala Ile Pro LeuVal Leu Ala Leu Phe Ala Phe 225 230 235 240 Val Gly Phe Met Leu Ile LeuVal Val Val Pro Leu Phe Val Trp Lys 245 250 255 Met Gly Arg Leu Leu GlnTyr Ser Cys Cys Pro Val Val Val Leu Pro 260 265 270 Asp Thr Leu Lys IleThr Asn Ser Pro Gln Lys Leu Ile Ser Cys Arg 275 280 285 Arg Glu Glu ValAsp Ala Cys Ala Thr Ala Val Met Ser Pro Glu Glu 290 295 300 Leu Leu ArgAla Trp Ile Ser 305 310 15 203 PRT Homo sapiens 15 Asp Glu Val Ala IleLeu Pro Ala Pro Gln Asn Leu Ser Val Leu Ser 1 5 10 15 Thr Asn Met LysHis Leu Leu Met Trp Ser Pro Val Ile Ala Pro Gly 20 25 30 Glu Thr Val TyrTyr Ser Val Glu Tyr Gln Gly Glu Tyr Glu Ser Leu 35 40 45 Tyr Thr Ser HisIle Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu 50 55 60 Gly Pro Glu CysAsp Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr 65 70 75 80 Asn Leu ArgVal Arg Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser 85 90 95 Ile Leu LysHis Pro Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro 100 105 110 Gly MetGlu Ile Thr Lys Asp Gly Phe His Leu Val Ile Glu Leu Glu 115 120 125 AspLeu Gly Pro Gln Phe Glu Phe Leu Val Ala Tyr Trp Arg Arg Glu 130 135 140Pro Gly Ala Glu Glu His Val Lys Met Val Arg Ser Gly Gly Ile Pro 145 150155 160 Val His Leu Glu Thr Met Glu Pro Gly Ala Ala Tyr Cys Val Lys Ala165 170 175 Gln Thr Phe Val Lys Ala Ile Gly Arg Tyr Ser Ala Phe Ser GlnThr 180 185 190 Glu Cys Val Glu Val Gln Gly Glu Ala Ile Pro 195 200 1633 DNA Homo sapiens 16 gcgaattcga gtctaccaaa tgcagacttt cac 33 17 32 DNAHomo sapiens 17 cgctcgagcc ttccgcaaac ctatgagatc ca 32 18 1382 DNA Homosapiens CDS (132)...(1034) 18 tcgacccacg cgtccgcgct gcgactcagacctcagctcc aacatatgca ttctgaagaa 60 agatggctga gatggacaga atgctttattttggaaagaa acaatgttct aggtcaaact 120 gagtctacca a atg cag act ttc acaatg gtt cta gaa gaa atc tgg aca 170 Met Gln Thr Phe Thr Met Val Leu GluGlu Ile Trp Thr 1 5 10 agt ctt ttc atg tgg ttt ttc tac gca ttg att ccatgt ttg ctc aca 218 Ser Leu Phe Met Trp Phe Phe Tyr Ala Leu Ile Pro CysLeu Leu Thr 15 20 25 gat gaa gtg gcc att ctg cct gcc cct cag aac ctc tctgta ctc tca 266 Asp Glu Val Ala Ile Leu Pro Ala Pro Gln Asn Leu Ser ValLeu Ser 30 35 40 45 acc aac atg aag cat ctc ttg atg tgg agc cca gtg atcgcg cct gga 314 Thr Asn Met Lys His Leu Leu Met Trp Ser Pro Val Ile AlaPro Gly 50 55 60 gaa aca gtg tac tat tct gtc gaa tac cag ggg gag tac gagagc ctg 362 Glu Thr Val Tyr Tyr Ser Val Glu Tyr Gln Gly Glu Tyr Glu SerLeu 65 70 75 tac acg agc cac atc tgg atc ccc agc agc tgg tgc tca ctc actgaa 410 Tyr Thr Ser His Ile Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu80 85 90 ggt cct gag tgt gat gtc act gat gac atc acg gcc act gtg cca tac458 Gly Pro Glu Cys Asp Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr 95100 105 aac ctt cgt gtc agg gcc aca ttg ggc tca cag acc tca gcc tgg agc506 Asn Leu Arg Val Arg Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser 110115 120 125 atc ctg aag cat ccc ttt aat aga aac tca acc atc ctt acc cgacct 554 Ile Leu Lys His Pro Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro130 135 140 ggg atg gag atc ccc aaa cat ggc ttc cac ctg gtt att gag ctggag 602 Gly Met Glu Ile Pro Lys His Gly Phe His Leu Val Ile Glu Leu Glu145 150 155 gac ctg ggg ccc cag ttt gag ttc ctt gtg gcc tac tgg acg agggag 650 Asp Leu Gly Pro Gln Phe Glu Phe Leu Val Ala Tyr Trp Thr Arg Glu160 165 170 cct ggt gcc gag gaa cat gtc aaa atg gtg agg agt ggg ggt attcca 698 Pro Gly Ala Glu Glu His Val Lys Met Val Arg Ser Gly Gly Ile Pro175 180 185 gtg cac cta gaa acc atg gag cca ggg gct gca tac tgt gtg aaggcc 746 Val His Leu Glu Thr Met Glu Pro Gly Ala Ala Tyr Cys Val Lys Ala190 195 200 205 cag aca ttc gtg aag gcc att ggg agg tac agc gcc ttc agccag aca 794 Gln Thr Phe Val Lys Ala Ile Gly Arg Tyr Ser Ala Phe Ser GlnThr 210 215 220 gaa tgt gtg gag gtg caa gga gag gcc att ccc ctg gta ctggcc ctg 842 Glu Cys Val Glu Val Gln Gly Glu Ala Ile Pro Leu Val Leu AlaLeu 225 230 235 ttt gcc ttt gtt ggc ttc atg ctg atc ctt gtg gtc gtg ccactg ttc 890 Phe Ala Phe Val Gly Phe Met Leu Ile Leu Val Val Val Pro LeuPhe 240 245 250 gtc tgg aaa atg ggc cgg ctg ctc cag tac tcc tgt tgc cccgtg gtg 938 Val Trp Lys Met Gly Arg Leu Leu Gln Tyr Ser Cys Cys Pro ValVal 255 260 265 gtc ctc cca gac acc ttg aaa ata acc aat tca ccc cag gttaat cag 986 Val Leu Pro Asp Thr Leu Lys Ile Thr Asn Ser Pro Gln Val AsnGln 270 275 280 285 ctg cag aag gga gga ggt gga tgc ctg tgc cac ggc tgtgat gtc tcc 1034 Leu Gln Lys Gly Gly Gly Gly Cys Leu Cys His Gly Cys AspVal Ser 290 295 300 tgaggaactc ctcagggcct ggatctcata tcaggtttgcggaagggccc aggtgaagcc 1094 gagaacctgg tctgcatgac atggaaacca tgaggggacaagttgtgttt ctgttttccg 1154 ccacggacaa gggatgagag aagtaggaag agcctgttgtctacaagtct agaagcaacc 1214 atcagaggca gggtggtttg tctaacagaa caactgactgaggctatggg ggttgtgacc 1274 tctagacttt gggcttccac ttgcttggct gagcaaccctgggaaaagtg acttcatccc 1334 ttcggtccca agttttctca tctgtaatgg gggatccctacaaaactg 1382 19 301 PRT Homo sapiens 19 Met Gln Thr Phe Thr Met Val LeuGlu Glu Ile Trp Thr Ser Leu Phe 1 5 10 15 Met Trp Phe Phe Tyr Ala LeuIle Pro Cys Leu Leu Thr Asp Glu Val 20 25 30 Ala Ile Leu Pro Ala Pro GlnAsn Leu Ser Val Leu Ser Thr Asn Met 35 40 45 Lys His Leu Leu Met Trp SerPro Val Ile Ala Pro Gly Glu Thr Val 50 55 60 Tyr Tyr Ser Val Glu Tyr GlnGly Glu Tyr Glu Ser Leu Tyr Thr Ser 65 70 75 80 His Ile Trp Ile Pro SerSer Trp Cys Ser Leu Thr Glu Gly Pro Glu 85 90 95 Cys Asp Val Thr Asp AspIle Thr Ala Thr Val Pro Tyr Asn Leu Arg 100 105 110 Val Arg Ala Thr LeuGly Ser Gln Thr Ser Ala Trp Ser Ile Leu Lys 115 120 125 His Pro Phe AsnArg Asn Ser Thr Ile Leu Thr Arg Pro Gly Met Glu 130 135 140 Ile Pro LysHis Gly Phe His Leu Val Ile Glu Leu Glu Asp Leu Gly 145 150 155 160 ProGln Phe Glu Phe Leu Val Ala Tyr Trp Thr Arg Glu Pro Gly Ala 165 170 175Glu Glu His Val Lys Met Val Arg Ser Gly Gly Ile Pro Val His Leu 180 185190 Glu Thr Met Glu Pro Gly Ala Ala Tyr Cys Val Lys Ala Gln Thr Phe 195200 205 Val Lys Ala Ile Gly Arg Tyr Ser Ala Phe Ser Gln Thr Glu Cys Val210 215 220 Glu Val Gln Gly Glu Ala Ile Pro Leu Val Leu Ala Leu Phe AlaPhe 225 230 235 240 Val Gly Phe Met Leu Ile Leu Val Val Val Pro Leu PheVal Trp Lys 245 250 255 Met Gly Arg Leu Leu Gln Tyr Ser Cys Cys Pro ValVal Val Leu Pro 260 265 270 Asp Thr Leu Lys Ile Thr Asn Ser Pro Gln ValAsn Gln Leu Gln Lys 275 280 285 Gly Gly Gly Gly Cys Leu Cys His Gly CysAsp Val Ser 290 295 300 20 1081 DNA Homo sapiens CDS (9)...(1067) 20ggccggcc atg cag act ttc aca atg gtt cta gaa gaa atc tgg aca agt 50 MetGln Thr Phe Thr Met Val Leu Glu Glu Ile Trp Thr Ser 1 5 10 ctt ttc atgtgg ttt ttc tac gca ttg att cca tgt ttg ctc aca gat 98 Leu Phe Met TrpPhe Phe Tyr Ala Leu Ile Pro Cys Leu Leu Thr Asp 15 20 25 30 gaa gtg gccatt ctg cct gcc cct cag aac ctc tct gta ctc tca acc 146 Glu Val Ala IleLeu Pro Ala Pro Gln Asn Leu Ser Val Leu Ser Thr 35 40 45 aac atg aag catctc ttg atg tgg agc cca gtg atc gcg cct gga gaa 194 Asn Met Lys His LeuLeu Met Trp Ser Pro Val Ile Ala Pro Gly Glu 50 55 60 aca gtg tac tat tctgtc gaa tac cag ggg gag tac gag agc ctg tac 242 Thr Val Tyr Tyr Ser ValGlu Tyr Gln Gly Glu Tyr Glu Ser Leu Tyr 65 70 75 acg agc cac atc tgg atcccc agc agc tgg tgc tca ctc act gaa ggt 290 Thr Ser His Ile Trp Ile ProSer Ser Trp Cys Ser Leu Thr Glu Gly 80 85 90 cct gag tgt gat gtc act gatgac atc acg gcc act gtg cca tac aac 338 Pro Glu Cys Asp Val Thr Asp AspIle Thr Ala Thr Val Pro Tyr Asn 95 100 105 110 ctt cgt gtc agg gcc acattg ggc tca cag acc tca gcc tgg agc atc 386 Leu Arg Val Arg Ala Thr LeuGly Ser Gln Thr Ser Ala Trp Ser Ile 115 120 125 ctg aag cat ccc ttt aataga aac tca acc atc ctt acc cga cct ggg 434 Leu Lys His Pro Phe Asn ArgAsn Ser Thr Ile Leu Thr Arg Pro Gly 130 135 140 atg gag atc ccc aaa catggc ttc cac ctg gtt att gag ctg gag gac 482 Met Glu Ile Pro Lys His GlyPhe His Leu Val Ile Glu Leu Glu Asp 145 150 155 ctg ggg ccc cag ttt gagttc ctt gtg gcc tac tgg acg agg gag cct 530 Leu Gly Pro Gln Phe Glu PheLeu Val Ala Tyr Trp Thr Arg Glu Pro 160 165 170 ggt gcc gag gaa cat gtcaaa atg gtg agg agt ggg ggt att cca gtg 578 Gly Ala Glu Glu His Val LysMet Val Arg Ser Gly Gly Ile Pro Val 175 180 185 190 cac cta gaa acc atggag cca ggg gct gca tac tgt gtg aag gcc cag 626 His Leu Glu Thr Met GluPro Gly Ala Ala Tyr Cys Val Lys Ala Gln 195 200 205 aca ttc gtg aag gccatt ggg agg tac agc gcc ttc agc cag aca gaa 674 Thr Phe Val Lys Ala IleGly Arg Tyr Ser Ala Phe Ser Gln Thr Glu 210 215 220 tgt gtg gag gtg caagga gag gcc gga ggt ggt ggc agt gga ggc ggc 722 Cys Val Glu Val Gln GlyGlu Ala Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 ggt agc gga ggc ggtggc agt cga act gtg gct gca cca tct gtc ttc 770 Gly Ser Gly Gly Gly GlySer Arg Thr Val Ala Ala Pro Ser Val Phe 240 245 250 atc ttc ccg cca tctgat gag cag ttg aaa tct gga act gcc tct gtt 818 Ile Phe Pro Pro Ser AspGlu Gln Leu Lys Ser Gly Thr Ala Ser Val 255 260 265 270 gtg tgc ctg ctgaat aac ttc tat ccc aga gag gcc aaa gta cag tgg 866 Val Cys Leu Leu AsnAsn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 275 280 285 aag gtg gat aacgcc ctc caa tcg ggt aac tcc cag gag agt gtc aca 914 Lys Val Asp Asn AlaLeu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 290 295 300 gag cag gac agcaag gac agc acc tac agc ctc agc agc acc ctg acg 962 Glu Gln Asp Ser LysAsp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 305 310 315 ctg agc aaa gcagac tac gag aaa cac aaa gtc tac gcc tgc gaa gtc 1010 Leu Ser Lys Ala AspTyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 320 325 330 acc cat cag ggcctg agc tcg ccc gtc aca aag agc ttc aac agg gga 1058 Thr His Gln Gly LeuSer Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 335 340 345 350 gag tgt taatctagaggcg cgcc 1081 Glu Cys * 21 352 PRT Homo sapiens 21 Met Gln ThrPhe Thr Met Val Leu Glu Glu Ile Trp Thr Ser Leu Phe 1 5 10 15 Met TrpPhe Phe Tyr Ala Leu Ile Pro Cys Leu Leu Thr Asp Glu Val 20 25 30 Ala IleLeu Pro Ala Pro Gln Asn Leu Ser Val Leu Ser Thr Asn Met 35 40 45 Lys HisLeu Leu Met Trp Ser Pro Val Ile Ala Pro Gly Glu Thr Val 50 55 60 Tyr TyrSer Val Glu Tyr Gln Gly Glu Tyr Glu Ser Leu Tyr Thr Ser 65 70 75 80 HisIle Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu Gly Pro Glu 85 90 95 CysAsp Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr Asn Leu Arg 100 105 110Val Arg Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser Ile Leu Lys 115 120125 His Pro Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro Gly Met Glu 130135 140 Ile Pro Lys His Gly Phe His Leu Val Ile Glu Leu Glu Asp Leu Gly145 150 155 160 Pro Gln Phe Glu Phe Leu Val Ala Tyr Trp Thr Arg Glu ProGly Ala 165 170 175 Glu Glu His Val Lys Met Val Arg Ser Gly Gly Ile ProVal His Leu 180 185 190 Glu Thr Met Glu Pro Gly Ala Ala Tyr Cys Val LysAla Gln Thr Phe 195 200 205 Val Lys Ala Ile Gly Arg Tyr Ser Ala Phe SerGln Thr Glu Cys Val 210 215 220 Glu Val Gln Gly Glu Ala Gly Gly Gly GlySer Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Arg Thr ValAla Ala Pro Ser Val Phe Ile Phe 245 250 255 Pro Pro Ser Asp Glu Gln LeuLys Ser Gly Thr Ala Ser Val Val Cys 260 265 270 Leu Leu Asn Asn Phe TyrPro Arg Glu Ala Lys Val Gln Trp Lys Val 275 280 285 Asp Asn Ala Leu GlnSer Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 290 295 300 Asp Ser Lys AspSer Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 305 310 315 320 Lys AlaAsp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 325 330 335 GlnGly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 340 345 35022 1801 DNA Homo sapiens CDS (8)...(1789) 22 gtcgacc atg gat gca atg aagaga ggg ctc tgc tgt gtg ctg ctg ctg 49 Met Asp Ala Met Lys Arg Gly LeuCys Cys Val Leu Leu Leu 1 5 10 tgt ggc gcc gtc ttc gtt tcg ctc agc caggaa atc cat gcc gag ttg 97 Cys Gly Ala Val Phe Val Ser Leu Ser Gln GluIle His Ala Glu Leu 15 20 25 30 aga cgc ttc cgt aga gtt ccc tgt gtc tctggt ggt ttg cct aaa cct 145 Arg Arg Phe Arg Arg Val Pro Cys Val Ser GlyGly Leu Pro Lys Pro 35 40 45 gca aac atc acc ttc tta tcc atc aac atg aagaat gtc cta caa tgg 193 Ala Asn Ile Thr Phe Leu Ser Ile Asn Met Lys AsnVal Leu Gln Trp 50 55 60 act cca cca gag ggt ctt caa gga gtt aaa gtt acttac act gtg cag 241 Thr Pro Pro Glu Gly Leu Gln Gly Val Lys Val Thr TyrThr Val Gln 65 70 75 tat ttc ata tat ggg caa aag aaa tgg ctg aat aaa tcagaa tgc aga 289 Tyr Phe Ile Tyr Gly Gln Lys Lys Trp Leu Asn Lys Ser GluCys Arg 80 85 90 aat atc aat aga acc tac tgt gat ctt tct gct gaa act tctgac tac 337 Asn Ile Asn Arg Thr Tyr Cys Asp Leu Ser Ala Glu Thr Ser AspTyr 95 100 105 110 gaa cac cag tat tat gcc aaa gtt aag gcc att tgg ggaaca aag tgt 385 Glu His Gln Tyr Tyr Ala Lys Val Lys Ala Ile Trp Gly ThrLys Cys 115 120 125 tcc aaa tgg gct gaa agt gga cgg ttc tat cct ttt ttagaa aca caa 433 Ser Lys Trp Ala Glu Ser Gly Arg Phe Tyr Pro Phe Leu GluThr Gln 130 135 140 att ggc cca cca gag gtg gca ctg act aca gat gag aagtcc att tct 481 Ile Gly Pro Pro Glu Val Ala Leu Thr Thr Asp Glu Lys SerIle Ser 145 150 155 gtt gtc ctg aca gct cca gag aag tgg aag aga aat ccagaa gac ctt 529 Val Val Leu Thr Ala Pro Glu Lys Trp Lys Arg Asn Pro GluAsp Leu 160 165 170 cct gtt tcc atg caa caa ata tac tcc aat ctg aag tataac gtg tct 577 Pro Val Ser Met Gln Gln Ile Tyr Ser Asn Leu Lys Tyr AsnVal Ser 175 180 185 190 gtg ttg aat act aaa tca aac aga acg tgg tcc cagtgt gtg acc aac 625 Val Leu Asn Thr Lys Ser Asn Arg Thr Trp Ser Gln CysVal Thr Asn 195 200 205 cac acg ctg gtg ctc acc tgg ctg gag ccg aac actctt tac tgc gta 673 His Thr Leu Val Leu Thr Trp Leu Glu Pro Asn Thr LeuTyr Cys Val 210 215 220 cac gtg gag tcc ttc gtc cca ggg ccc cct cgc cgtgct cag cct tct 721 His Val Glu Ser Phe Val Pro Gly Pro Pro Arg Arg AlaGln Pro Ser 225 230 235 gag aag cag tgt gcc agg act ttg aaa gat caa ggtgga ggc ggt tca 769 Glu Lys Gln Cys Ala Arg Thr Leu Lys Asp Gln Gly GlyGly Gly Ser 240 245 250 ggc gga ggt ggc tct ggc ggt ggc gga tcg gcc tccacc aag ggc cca 817 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser ThrLys Gly Pro 255 260 265 270 tcg gtc ttc ccc ctg gca ccc tcc tcc aag agcacc tct ggg ggc aca 865 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser ThrSer Gly Gly Thr 275 280 285 gcg gcc ctg ggc tgc ctg gtc aag gac tac ttcccc gaa ccg gtg acg 913 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe ProGlu Pro Val Thr 290 295 300 gtg tcg tgg aac tca ggc gcc ctg acc agc ggcgtg cac acc ttc ccg 961 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly ValHis Thr Phe Pro 305 310 315 gct gtc cta cag tcc tca gga ctc tac tcc ctcagc agc gtg gtg acc 1009 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu SerSer Val Val Thr 320 325 330 gtg ccc tcc agc agc ttg ggc acc cag acc tacatc tgc aac gtg aat 1057 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr IleCys Asn Val Asn 335 340 345 350 cac aag ccc agc aac acc aag gtg gac aagaaa gtt gag ccc aaa tct 1105 His Lys Pro Ser Asn Thr Lys Val Asp Lys LysVal Glu Pro Lys Ser 355 360 365 tgt gac aaa act cac aca tgc cca ccg tgccca gca cct gaa gcc gag 1153 Cys Asp Lys Thr His Thr Cys Pro Pro Cys ProAla Pro Glu Ala Glu 370 375 380 ggg gca ccg tca gtc ttc ctc ttc ccc ccaaaa ccc aag gac acc ctc 1201 Gly Ala Pro Ser Val Phe Leu Phe Pro Pro LysPro Lys Asp Thr Leu 385 390 395 atg atc tcc cgg acc cct gag gtc aca tgcgtg gtg gtg gac gtg agc 1249 Met Ile Ser Arg Thr Pro Glu Val Thr Cys ValVal Val Asp Val Ser 400 405 410 cac gaa gac cct gag gtc aag ttc aac tggtac gtg gac ggc gtg gag 1297 His Glu Asp Pro Glu Val Lys Phe Asn Trp TyrVal Asp Gly Val Glu 415 420 425 430 gtg cat aat gcc aag aca aag ccg cgggag gag cag tac aac agc acg 1345 Val His Asn Ala Lys Thr Lys Pro Arg GluGlu Gln Tyr Asn Ser Thr 435 440 445 tac cgt gtg gtc agc gtc ctc acc gtcctg cac cag gac tgg ctg aat 1393 Tyr Arg Val Val Ser Val Leu Thr Val LeuHis Gln Asp Trp Leu Asn 450 455 460 ggc aag gag tac aag tgc aag gtc tccaac aaa gcc ctc cca tcc tcc 1441 Gly Lys Glu Tyr Lys Cys Lys Val Ser AsnLys Ala Leu Pro Ser Ser 465 470 475 atc gag aaa acc atc tcc aaa gcc aaaggg cag ccc cga gaa cca cag 1489 Ile Glu Lys Thr Ile Ser Lys Ala Lys GlyGln Pro Arg Glu Pro Gln 480 485 490 gtg tac acc ctg ccc cca tcc cgg gatgag ctg acc aag aac cag gtc 1537 Val Tyr Thr Leu Pro Pro Ser Arg Asp GluLeu Thr Lys Asn Gln Val 495 500 505 510 agc ctg acc tgc ctg gtc aaa ggcttc tat ccc agc gac atc gcc gtg 1585 Ser Leu Thr Cys Leu Val Lys Gly PheTyr Pro Ser Asp Ile Ala Val 515 520 525 gag tgg gag agc aat ggg cag ccggag aac aac tac aag acc acg cct 1633 Glu Trp Glu Ser Asn Gly Gln Pro GluAsn Asn Tyr Lys Thr Thr Pro 530 535 540 ccc gtg ctg gac tcc gac ggc tccttc ttc ctc tac agc aag ctc acc 1681 Pro Val Leu Asp Ser Asp Gly Ser PhePhe Leu Tyr Ser Lys Leu Thr 545 550 555 gtg gac aag agc agg tgg cag cagggg aac gtc ttc tca tgc tcc gtg 1729 Val Asp Lys Ser Arg Trp Gln Gln GlyAsn Val Phe Ser Cys Ser Val 560 565 570 atg cat gag gct ctg cac aac cactac acg cag aag agc ctc tcc ctg 1777 Met His Glu Ala Leu His Asn His TyrThr Gln Lys Ser Leu Ser Leu 575 580 585 590 tct ccg ggt aaa taatctagatct 1801 Ser Pro Gly Lys 23 594 PRT Homo sapiens 23 Met Asp Ala Met LysArg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe ValSer Leu Ser Gln Glu Ile His Ala Glu Leu Arg Arg 20 25 30 Phe Arg Arg ValPro Cys Val Ser Gly Gly Leu Pro Lys Pro Ala Asn 35 40 45 Ile Thr Phe LeuSer Ile Asn Met Lys Asn Val Leu Gln Trp Thr Pro 50 55 60 Pro Glu Gly LeuGln Gly Val Lys Val Thr Tyr Thr Val Gln Tyr Phe 65 70 75 80 Ile Tyr GlyGln Lys Lys Trp Leu Asn Lys Ser Glu Cys Arg Asn Ile 85 90 95 Asn Arg ThrTyr Cys Asp Leu Ser Ala Glu Thr Ser Asp Tyr Glu His 100 105 110 Gln TyrTyr Ala Lys Val Lys Ala Ile Trp Gly Thr Lys Cys Ser Lys 115 120 125 TrpAla Glu Ser Gly Arg Phe Tyr Pro Phe Leu Glu Thr Gln Ile Gly 130 135 140Pro Pro Glu Val Ala Leu Thr Thr Asp Glu Lys Ser Ile Ser Val Val 145 150155 160 Leu Thr Ala Pro Glu Lys Trp Lys Arg Asn Pro Glu Asp Leu Pro Val165 170 175 Ser Met Gln Gln Ile Tyr Ser Asn Leu Lys Tyr Asn Val Ser ValLeu 180 185 190 Asn Thr Lys Ser Asn Arg Thr Trp Ser Gln Cys Val Thr AsnHis Thr 195 200 205 Leu Val Leu Thr Trp Leu Glu Pro Asn Thr Leu Tyr CysVal His Val 210 215 220 Glu Ser Phe Val Pro Gly Pro Pro Arg Arg Ala GlnPro Ser Glu Lys 225 230 235 240 Gln Cys Ala Arg Thr Leu Lys Asp Gln GlyGly Gly Gly Ser Gly Gly 245 250 255 Gly Gly Ser Gly Gly Gly Gly Ser AlaSer Thr Lys Gly Pro Ser Val 260 265 270 Phe Pro Leu Ala Pro Ser Ser LysSer Thr Ser Gly Gly Thr Ala Ala 275 280 285 Leu Gly Cys Leu Val Lys AspTyr Phe Pro Glu Pro Val Thr Val Ser 290 295 300 Trp Asn Ser Gly Ala LeuThr Ser Gly Val His Thr Phe Pro Ala Val 305 310 315 320 Leu Gln Ser SerGly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 325 330 335 Ser Ser SerLeu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 340 345 350 Pro SerAsn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 355 360 365 LysThr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Glu Gly Ala 370 375 380Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 385 390395 400 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu405 410 415 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu ValHis 420 425 430 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser ThrTyr Arg 435 440 445 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp LeuAsn Gly Lys 450 455 460 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu ProSer Ser Ile Glu 465 470 475 480 Lys Thr Ile Ser Lys Ala Lys Gly Gln ProArg Glu Pro Gln Val Tyr 485 490 495 Thr Leu Pro Pro Ser Arg Asp Glu LeuThr Lys Asn Gln Val Ser Leu 500 505 510 Thr Cys Leu Val Lys Gly Phe TyrPro Ser Asp Ile Ala Val Glu Trp 515 520 525 Glu Ser Asn Gly Gln Pro GluAsn Asn Tyr Lys Thr Thr Pro Pro Val 530 535 540 Leu Asp Ser Asp Gly SerPhe Phe Leu Tyr Ser Lys Leu Thr Val Asp 545 550 555 560 Lys Ser Arg TrpGln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 565 570 575 Glu Ala LeuHis Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 580 585 590 Gly Lys24 29 DNA Homo sapiens 24 ggccggccat gcagactttc acaatggtt 29 25 52 DNAhomo sapiens 25 tccgctaccg ccgcctccac tgccaccacc tccggcctct ccttgcacctcc 52 26 53 DNA Homo sapiens 26 gtggaggcgg cggtagcgga ggcggtggcagtcgaactgt ggctgcacca tct 53 27 38 DNA Homo sapiens 27 ggcgcgcctctagattaaca ctctcccctg ttgaagct 38 28 30 DNA Homo sapiens 28 gtcgaccatggatgcaatga agagagggct 30 29 30 DNA Homo sapiens 29 cacagggaac tctacggaagcgtctcaact 30 30 33 DNA Homo sapiens 30 cttccgtaga gttccctgtg tctctggtggttt 33 31 53 DNA Homo sapiens 31 gccagagcca cctccgcctg aaccgcctccaccttgatct ttcaaagtcc tgg 53 32 51 DNA Homo sapiens 32 caggcggaggtggctctggc ggtggcggat cggcctccac caagggccca t 51 33 20 DNA Homo sapiens33 ctgggcacgg tgggcatgtg 20 34 20 DNA Homo sapiens 34 cacatgcccaccgtgcccag 20 35 31 DNA Homo sapiens 35 agatctagat tatttacccg gagacagggag 31 36 1806 DNA Mus musculus CDS (38)...(1675) 36 cgccgcgttc ccgagatgtgacccgaactg acagccc atg cac act ccc ggg acc 55 Met His Thr Pro Gly Thr 15 ccg gcg ccg ggc cac ccg gac ccg ccg cca ctg ttg ctg ctc acg ctg 103Pro Ala Pro Gly His Pro Asp Pro Pro Pro Leu Leu Leu Leu Thr Leu 10 15 20ctt ctg ctg ctg gcc gct tcg gga cgc gca gtt cct tgt gtc ttc tgt 151 LeuLeu Leu Leu Ala Ala Ser Gly Arg Ala Val Pro Cys Val Phe Cys 25 30 35 ggtttg cct aaa cct aca aat atc acc ttc tta tcc atc aac atg aag 199 Gly LeuPro Lys Pro Thr Asn Ile Thr Phe Leu Ser Ile Asn Met Lys 40 45 50 aat gtcctg cat tgg aat cca cca gag agt cta cac gga gtt gaa gtc 247 Asn Val LeuHis Trp Asn Pro Pro Glu Ser Leu His Gly Val Glu Val 55 60 65 70 aca tacact gtg caa tat ttc ata tat ggg cag aag aaa tgg ctg aat 295 Thr Tyr ThrVal Gln Tyr Phe Ile Tyr Gly Gln Lys Lys Trp Leu Asn 75 80 85 gcc tct aaatgc ggg agt atc aac agg acc tac tgt gac ctt tct gtt 343 Ala Ser Lys CysGly Ser Ile Asn Arg Thr Tyr Cys Asp Leu Ser Val 90 95 100 gag acc tcagac tat gaa cac cag ttc tat gcc aaa gtg aag gcc att 391 Glu Thr Ser AspTyr Glu His Gln Phe Tyr Ala Lys Val Lys Ala Ile 105 110 115 tgg gaa gccagg tgc tcc gaa tgg gcc gag acg gaa cgc ttc tat cct 439 Trp Glu Ala ArgCys Ser Glu Trp Ala Glu Thr Glu Arg Phe Tyr Pro 120 125 130 ttc ttg gaaact caa gtc agc cca cca gag att gcc ctg aca act ggc 487 Phe Leu Glu ThrGln Val Ser Pro Pro Glu Ile Ala Leu Thr Thr Gly 135 140 145 150 gag aagtcc atc tct att gcc ctg aca gca cca gag aag tgg aaa aga 535 Glu Lys SerIle Ser Ile Ala Leu Thr Ala Pro Glu Lys Trp Lys Arg 155 160 165 aat ccacaa gac cac act gtt tct atg caa cag ata tac ccc aat ttg 583 Asn Pro GlnAsp His Thr Val Ser Met Gln Gln Ile Tyr Pro Asn Leu 170 175 180 aag tacaat gtg tct gtg tat aac act aag tcg aga aga acg tgg tcc 631 Lys Tyr AsnVal Ser Val Tyr Asn Thr Lys Ser Arg Arg Thr Trp Ser 185 190 195 cag tgtgtc acc aac agc aca ctg gtc ctc agc tgg ctg gag ccc aac 679 Gln Cys ValThr Asn Ser Thr Leu Val Leu Ser Trp Leu Glu Pro Asn 200 205 210 act ctgtat tgt gtc cac gtg gag tcc ctt gtc cca ggg ccc cct cgc 727 Thr Leu TyrCys Val His Val Glu Ser Leu Val Pro Gly Pro Pro Arg 215 220 225 230 ctcccg atg cct tct cag aag cag tgc atc agt act ttg gaa gtt caa 775 Leu ProMet Pro Ser Gln Lys Gln Cys Ile Ser Thr Leu Glu Val Gln 235 240 245 acatca gca tgg aag gct aaa gtc atc ttc tgg tat gtc ttc ctc aca 823 Thr SerAla Trp Lys Ala Lys Val Ile Phe Trp Tyr Val Phe Leu Thr 250 255 260 tctgtt atc gtg ttt ctt ttc tcc gca att ggc tac ttg gtt tac cgt 871 Ser ValIle Val Phe Leu Phe Ser Ala Ile Gly Tyr Leu Val Tyr Arg 265 270 275 tacatc cat gtt ggc aag gaa aaa cac cca gca aat ttg gta ctg att 919 Tyr IleHis Val Gly Lys Glu Lys His Pro Ala Asn Leu Val Leu Ile 280 285 290 tataga aat gaa att ggc aca aga gtc ttt gaa cct act gaa aca atc 967 Tyr ArgAsn Glu Ile Gly Thr Arg Val Phe Glu Pro Thr Glu Thr Ile 295 300 305 310aca ctt aat ttt atc acc ttc agt atg ttg gat gat act aaa att tct 1015 ThrLeu Asn Phe Ile Thr Phe Ser Met Leu Asp Asp Thr Lys Ile Ser 315 320 325cca aag gat atg aat tta ctg gac aaa agc agt gat gac atc agt gtt 1063 ProLys Asp Met Asn Leu Leu Asp Lys Ser Ser Asp Asp Ile Ser Val 330 335 340aat gac cct gag cac aat gag gcc tgg gag ccg cac tgg gag gag gtg 1111 AsnAsp Pro Glu His Asn Glu Ala Trp Glu Pro His Trp Glu Glu Val 345 350 355gag ggg caa cat tta gga tgc tct tcg cat ttg atg gac gct gtc tgt 1159 GluGly Gln His Leu Gly Cys Ser Ser His Leu Met Asp Ala Val Cys 360 365 370ggt gct gag caa aga gac gga gac acc tcc cta acc cag cat ggg tgg 1207 GlyAla Glu Gln Arg Asp Gly Asp Thr Ser Leu Thr Gln His Gly Trp 375 380 385390 ctt aac agc acc atc ccc aca gga gag aca gac act gag cct caa tac 1255Leu Asn Ser Thr Ile Pro Thr Gly Glu Thr Asp Thr Glu Pro Gln Tyr 395 400405 aaa gtc cta agt gac ttc tac ggg gag ggt gaa atc caa ctg tcc tgt 1303Lys Val Leu Ser Asp Phe Tyr Gly Glu Gly Glu Ile Gln Leu Ser Cys 410 415420 gag ccg gaa gag gcg gcc aga aca gag aaa ata tct gag cca ctg gtg 1351Glu Pro Glu Glu Ala Ala Arg Thr Glu Lys Ile Ser Glu Pro Leu Val 425 430435 act tca gca aac ttg gac cca cag ctt gaa gac cta cat cac ctg ggt 1399Thr Ser Ala Asn Leu Asp Pro Gln Leu Glu Asp Leu His His Leu Gly 440 445450 cag gag cat act gtc tcc gag gat ggg cca gag gaa gag aca tct ata 1447Gln Glu His Thr Val Ser Glu Asp Gly Pro Glu Glu Glu Thr Ser Ile 455 460465 470 aca gta gtg gat tgg gac cct caa act ggc agg ctg tgt atc cct tcc1495 Thr Val Val Asp Trp Asp Pro Gln Thr Gly Arg Leu Cys Ile Pro Ser 475480 485 tta cct atc ttt ggc cgt gat cct gag aac tat ggt cat tat gag aga1543 Leu Pro Ile Phe Gly Arg Asp Pro Glu Asn Tyr Gly His Tyr Glu Arg 490495 500 gac cag ctc tta gag ggt ggc ctt ttg tct aga ctc tat gag aac cag1591 Asp Gln Leu Leu Glu Gly Gly Leu Leu Ser Arg Leu Tyr Glu Asn Gln 505510 515 gca cct gac aag cca gag aaa gaa aat gaa aac tgt ctc aca cgg ttt1639 Ala Pro Asp Lys Pro Glu Lys Glu Asn Glu Asn Cys Leu Thr Arg Phe 520525 530 atg gag gaa tgg ggg tta cat gta caa atg gaa agc tagtgccagg 1685Met Glu Glu Trp Gly Leu His Val Gln Met Glu Ser 535 540 545 ctttctgttgactgccaaca aatgaaggaa ccatcccagg gggtgaacag tgttcaggtt 1745 atcagtgtcagcaatgagac tgttctctct gttcatgaac tttgtcagcc ctgcctcatc 1805 c 1806 37546 PRT Mus musculus 37 Met His Thr Pro Gly Thr Pro Ala Pro Gly His ProAsp Pro Pro Pro 1 5 10 15 Leu Leu Leu Leu Thr Leu Leu Leu Leu Leu AlaAla Ser Gly Arg Ala 20 25 30 Val Pro Cys Val Phe Cys Gly Leu Pro Lys ProThr Asn Ile Thr Phe 35 40 45 Leu Ser Ile Asn Met Lys Asn Val Leu His TrpAsn Pro Pro Glu Ser 50 55 60 Leu His Gly Val Glu Val Thr Tyr Thr Val GlnTyr Phe Ile Tyr Gly 65 70 75 80 Gln Lys Lys Trp Leu Asn Ala Ser Lys CysGly Ser Ile Asn Arg Thr 85 90 95 Tyr Cys Asp Leu Ser Val Glu Thr Ser AspTyr Glu His Gln Phe Tyr 100 105 110 Ala Lys Val Lys Ala Ile Trp Glu AlaArg Cys Ser Glu Trp Ala Glu 115 120 125 Thr Glu Arg Phe Tyr Pro Phe LeuGlu Thr Gln Val Ser Pro Pro Glu 130 135 140 Ile Ala Leu Thr Thr Gly GluLys Ser Ile Ser Ile Ala Leu Thr Ala 145 150 155 160 Pro Glu Lys Trp LysArg Asn Pro Gln Asp His Thr Val Ser Met Gln 165 170 175 Gln Ile Tyr ProAsn Leu Lys Tyr Asn Val Ser Val Tyr Asn Thr Lys 180 185 190 Ser Arg ArgThr Trp Ser Gln Cys Val Thr Asn Ser Thr Leu Val Leu 195 200 205 Ser TrpLeu Glu Pro Asn Thr Leu Tyr Cys Val His Val Glu Ser Leu 210 215 220 ValPro Gly Pro Pro Arg Leu Pro Met Pro Ser Gln Lys Gln Cys Ile 225 230 235240 Ser Thr Leu Glu Val Gln Thr Ser Ala Trp Lys Ala Lys Val Ile Phe 245250 255 Trp Tyr Val Phe Leu Thr Ser Val Ile Val Phe Leu Phe Ser Ala Ile260 265 270 Gly Tyr Leu Val Tyr Arg Tyr Ile His Val Gly Lys Glu Lys HisPro 275 280 285 Ala Asn Leu Val Leu Ile Tyr Arg Asn Glu Ile Gly Thr ArgVal Phe 290 295 300 Glu Pro Thr Glu Thr Ile Thr Leu Asn Phe Ile Thr PheSer Met Leu 305 310 315 320 Asp Asp Thr Lys Ile Ser Pro Lys Asp Met AsnLeu Leu Asp Lys Ser 325 330 335 Ser Asp Asp Ile Ser Val Asn Asp Pro GluHis Asn Glu Ala Trp Glu 340 345 350 Pro His Trp Glu Glu Val Glu Gly GlnHis Leu Gly Cys Ser Ser His 355 360 365 Leu Met Asp Ala Val Cys Gly AlaGlu Gln Arg Asp Gly Asp Thr Ser 370 375 380 Leu Thr Gln His Gly Trp LeuAsn Ser Thr Ile Pro Thr Gly Glu Thr 385 390 395 400 Asp Thr Glu Pro GlnTyr Lys Val Leu Ser Asp Phe Tyr Gly Glu Gly 405 410 415 Glu Ile Gln LeuSer Cys Glu Pro Glu Glu Ala Ala Arg Thr Glu Lys 420 425 430 Ile Ser GluPro Leu Val Thr Ser Ala Asn Leu Asp Pro Gln Leu Glu 435 440 445 Asp LeuHis His Leu Gly Gln Glu His Thr Val Ser Glu Asp Gly Pro 450 455 460 GluGlu Glu Thr Ser Ile Thr Val Val Asp Trp Asp Pro Gln Thr Gly 465 470 475480 Arg Leu Cys Ile Pro Ser Leu Pro Ile Phe Gly Arg Asp Pro Glu Asn 485490 495 Tyr Gly His Tyr Glu Arg Asp Gln Leu Leu Glu Gly Gly Leu Leu Ser500 505 510 Arg Leu Tyr Glu Asn Gln Ala Pro Asp Lys Pro Glu Lys Glu AsnGlu 515 520 525 Asn Cys Leu Thr Arg Phe Met Glu Glu Trp Gly Leu His ValGln Met 530 535 540 Glu Ser 545 38 217 PRT Mus musculus 38 Val Pro CysVal Phe Cys Gly Leu Pro Lys Pro Thr Asn Ile Thr Phe 1 5 10 15 Leu SerIle Asn Met Lys Asn Val Leu His Trp Asn Pro Pro Glu Ser 20 25 30 Leu HisGly Val Glu Val Thr Tyr Thr Val Gln Tyr Phe Ile Tyr Gly 35 40 45 Gln LysLys Trp Leu Asn Ala Ser Lys Cys Gly Ser Ile Asn Arg Thr 50 55 60 Tyr CysAsp Leu Ser Val Glu Thr Ser Asp Tyr Glu His Gln Phe Tyr 65 70 75 80 AlaLys Val Lys Ala Ile Trp Glu Ala Arg Cys Ser Glu Trp Ala Glu 85 90 95 ThrGlu Arg Phe Tyr Pro Phe Leu Glu Thr Gln Val Ser Pro Pro Glu 100 105 110Ile Ala Leu Thr Thr Gly Glu Lys Ser Ile Ser Ile Ala Leu Thr Ala 115 120125 Pro Glu Lys Trp Lys Arg Asn Pro Gln Asp His Thr Val Ser Met Gln 130135 140 Gln Ile Tyr Pro Asn Leu Lys Tyr Asn Val Ser Val Tyr Asn Thr Lys145 150 155 160 Ser Arg Arg Thr Trp Ser Gln Cys Val Thr Asn Ser Thr LeuVal Leu 165 170 175 Ser Trp Leu Glu Pro Asn Thr Leu Tyr Cys Val His ValGlu Ser Leu 180 185 190 Val Pro Gly Pro Pro Arg Leu Pro Met Pro Ser GlnLys Gln Cys Ile 195 200 205 Ser Thr Leu Glu Val Gln Thr Ser Ala 210 21539 514 PRT Mus musculus 39 Val Pro Cys Val Phe Cys Gly Leu Pro Lys ProThr Asn Ile Thr Phe 1 5 10 15 Leu Ser Ile Asn Met Lys Asn Val Leu HisTrp Asn Pro Pro Glu Ser 20 25 30 Leu His Gly Val Glu Val Thr Tyr Thr ValGln Tyr Phe Ile Tyr Gly 35 40 45 Gln Lys Lys Trp Leu Asn Ala Ser Lys CysGly Ser Ile Asn Arg Thr 50 55 60 Tyr Cys Asp Leu Ser Val Glu Thr Ser AspTyr Glu His Gln Phe Tyr 65 70 75 80 Ala Lys Val Lys Ala Ile Trp Glu AlaArg Cys Ser Glu Trp Ala Glu 85 90 95 Thr Glu Arg Phe Tyr Pro Phe Leu GluThr Gln Val Ser Pro Pro Glu 100 105 110 Ile Ala Leu Thr Thr Gly Glu LysSer Ile Ser Ile Ala Leu Thr Ala 115 120 125 Pro Glu Lys Trp Lys Arg AsnPro Gln Asp His Thr Val Ser Met Gln 130 135 140 Gln Ile Tyr Pro Asn LeuLys Tyr Asn Val Ser Val Tyr Asn Thr Lys 145 150 155 160 Ser Arg Arg ThrTrp Ser Gln Cys Val Thr Asn Ser Thr Leu Val Leu 165 170 175 Ser Trp LeuGlu Pro Asn Thr Leu Tyr Cys Val His Val Glu Ser Leu 180 185 190 Val ProGly Pro Pro Arg Leu Pro Met Pro Ser Gln Lys Gln Cys Ile 195 200 205 SerThr Leu Glu Val Gln Thr Ser Ala Trp Lys Ala Lys Val Ile Phe 210 215 220Trp Tyr Val Phe Leu Thr Ser Val Ile Val Phe Leu Phe Ser Ala Ile 225 230235 240 Gly Tyr Leu Val Tyr Arg Tyr Ile His Val Gly Lys Glu Lys His Pro245 250 255 Ala Asn Leu Val Leu Ile Tyr Arg Asn Glu Ile Gly Thr Arg ValPhe 260 265 270 Glu Pro Thr Glu Thr Ile Thr Leu Asn Phe Ile Thr Phe SerMet Leu 275 280 285 Asp Asp Thr Lys Ile Ser Pro Lys Asp Met Asn Leu LeuAsp Lys Ser 290 295 300 Ser Asp Asp Ile Ser Val Asn Asp Pro Glu His AsnGlu Ala Trp Glu 305 310 315 320 Pro His Trp Glu Glu Val Glu Gly Gln HisLeu Gly Cys Ser Ser His 325 330 335 Leu Met Asp Ala Val Cys Gly Ala GluGln Arg Asp Gly Asp Thr Ser 340 345 350 Leu Thr Gln His Gly Trp Leu AsnSer Thr Ile Pro Thr Gly Glu Thr 355 360 365 Asp Thr Glu Pro Gln Tyr LysVal Leu Ser Asp Phe Tyr Gly Glu Gly 370 375 380 Glu Ile Gln Leu Ser CysGlu Pro Glu Glu Ala Ala Arg Thr Glu Lys 385 390 395 400 Ile Ser Glu ProLeu Val Thr Ser Ala Asn Leu Asp Pro Gln Leu Glu 405 410 415 Asp Leu HisHis Leu Gly Gln Glu His Thr Val Ser Glu Asp Gly Pro 420 425 430 Glu GluGlu Thr Ser Ile Thr Val Val Asp Trp Asp Pro Gln Thr Gly 435 440 445 ArgLeu Cys Ile Pro Ser Leu Pro Ile Phe Gly Arg Asp Pro Glu Asn 450 455 460Tyr Gly His Tyr Glu Arg Asp Gln Leu Leu Glu Gly Gly Leu Leu Ser 465 470475 480 Arg Leu Tyr Glu Asn Gln Ala Pro Asp Lys Pro Glu Lys Glu Asn Glu485 490 495 Asn Cys Leu Thr Arg Phe Met Glu Glu Trp Gly Leu His Val GlnMet 500 505 510 Glu Ser 40 18 DNA Mus musculus 40 cgccgcgttc ccgagatg 1841 24 DNA Mus musculus 41 ggatgaggca gggctgacaa agtt 24 42 36 DNA Homosapiens 42 acttgtggaa ttcgctagca ccaagggccc atcggt 36 43 32 DNA Homosapiens 43 gcctagaacg cgttcattta cccggagaca gg 32 44 8 DNA Homo sapiens44 aattgaga 8 45 8 DNA Homo sapiens 45 cgcgtctc 8 46 37 DNA Homo sapiens46 gtcacttgaa ttcggtaccg cctctgttgt gtgcctg 37 47 32 DNA Homo sapiens 47gacctgaacg cgtctaacac tctcccctgt tg 32 48 38 DNA Homo sapiens 48tcagtcggaa ttcgcagaag ccatgcgggc tcccggcc 38 49 35 DNA Homo sapiens 49ctgtgacgct agcctctgat gattgatctt tcaaa 35 50 43 DNA Homo sapiens 50gatgtctgaa ttcgcagaag ccatgcagac tttcacaatg gtt 43 51 86 DNA Homosapiens 51 aagacggtac cagatttcaa ctgctcatca gatggcggga agatgaagacagatggtgca 60 gccacagtgg cctctccttg cacctc 86 52 1720 DNA Homo sapiensCDS (1)...(1713) 52 atg cgg gct ccc ggc cgc ccg gcc ctg cgg ccg ctg ctgctg ttg ctc 48 Met Arg Ala Pro Gly Arg Pro Ala Leu Arg Pro Leu Leu LeuLeu Leu 1 5 10 15 ctg gcg gcg cct tgg gga cgg gca gtt ccc tgt gtc tctggt ggt ttg 96 Leu Ala Ala Pro Trp Gly Arg Ala Val Pro Cys Val Ser GlyGly Leu 20 25 30 cct aaa cct gca aac atc acc ttc tta tcc atc aac atg aagaat gtc 144 Pro Lys Pro Ala Asn Ile Thr Phe Leu Ser Ile Asn Met Lys AsnVal 35 40 45 cta caa tgg act cca cca gag ggt ctt caa gga gtt aaa gtt acttac 192 Leu Gln Trp Thr Pro Pro Glu Gly Leu Gln Gly Val Lys Val Thr Tyr50 55 60 act gtg cag tat ttc ata tat ggg caa aag aaa tgg ctg aat aaa tca240 Thr Val Gln Tyr Phe Ile Tyr Gly Gln Lys Lys Trp Leu Asn Lys Ser 6570 75 80 gaa tgc aga aat atc aat aga acc tac tgt gat ctt tct gct gaa act288 Glu Cys Arg Asn Ile Asn Arg Thr Tyr Cys Asp Leu Ser Ala Glu Thr 8590 95 tct gac tac gaa cac cag tat tat gcc aaa gtt aag gcc att tgg gga336 Ser Asp Tyr Glu His Gln Tyr Tyr Ala Lys Val Lys Ala Ile Trp Gly 100105 110 aca aag tgt tcc aaa tgg gct gaa agt gga cgg ttc tat cct ttt tta384 Thr Lys Cys Ser Lys Trp Ala Glu Ser Gly Arg Phe Tyr Pro Phe Leu 115120 125 gaa aca caa att ggc cca cca gag gtg gca ctg act aca gat gag aag432 Glu Thr Gln Ile Gly Pro Pro Glu Val Ala Leu Thr Thr Asp Glu Lys 130135 140 tcc att tct gtt gtc ctg aca gct cca gag aag tgg aag aga aat cca480 Ser Ile Ser Val Val Leu Thr Ala Pro Glu Lys Trp Lys Arg Asn Pro 145150 155 160 gaa gac ctt cct gtt tcc atg caa caa ata tac tcc aat ctg aagtat 528 Glu Asp Leu Pro Val Ser Met Gln Gln Ile Tyr Ser Asn Leu Lys Tyr165 170 175 aac gtg tct gtg ttg aat act aaa tca aac aga acg tgg tcc cagtgt 576 Asn Val Ser Val Leu Asn Thr Lys Ser Asn Arg Thr Trp Ser Gln Cys180 185 190 gtg acc aac cac acg ctg gtg ctc acc tgg ctg gag ccg aac actctt 624 Val Thr Asn His Thr Leu Val Leu Thr Trp Leu Glu Pro Asn Thr Leu195 200 205 tac tgc gta cac gtg gag tcc ttc gtc cca ggg ccc cct cgc cgtgct 672 Tyr Cys Val His Val Glu Ser Phe Val Pro Gly Pro Pro Arg Arg Ala210 215 220 cag cct tct gag aag cag tgt gcc agg act ttg aaa gat caa tcatca 720 Gln Pro Ser Glu Lys Gln Cys Ala Arg Thr Leu Lys Asp Gln Ser Ser225 230 235 240 gag gct agc acc aag ggc cca tcg gtc ttc ccc ctg gca ccctcc tcc 768 Glu Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro SerSer 245 250 255 aag agc acc tct ggg ggc aca gcg gcc ctg ggc tgc ctg gtcaag gac 816 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val LysAsp 260 265 270 tac ttc ccc gaa ccg gtg acg gtg tcg tgg aac tca ggc gccctg acc 864 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala LeuThr 275 280 285 agc ggc gtg cac acc ttc ccg gct gtc cta cag tcc tca ggactc tac 912 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly LeuTyr 290 295 300 tcc ctc agc agc gtg gtg acc gtg ccc tcc agc agc ttg ggcacc cag 960 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly ThrGln 305 310 315 320 acc tac atc tgc aac gtg aat cac aag ccc agc aac accaag gtg gac 1008 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr LysVal Asp 325 330 335 aag aaa gtt gag ccc aaa tct tgt gac aaa act cac acatgc cca ccg 1056 Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr CysPro Pro 340 345 350 tgc cca gca cct gaa ctc ctg ggg gga ccg tca gtc ttcctc ttc ccc 1104 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe LeuPhe Pro 355 360 365 cca aaa ccc aag gac acc ctc atg atc tcc cgg acc cctgag gtc aca 1152 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro GluVal Thr 370 375 380 tgc gtg gtg gtg gac gtg agc cac gaa gac cct gag gtcaag ttc aac 1200 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val LysPhe Asn 385 390 395 400 tgg tac gtg gac ggc gtg gag gtg cat aat gcc aagaca aag ccg cgg 1248 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys ThrLys Pro Arg 405 410 415 gag gag cag tac aac agc acg tac cgt gtg gtc agcgtc ctc acc gtc 1296 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser ValLeu Thr Val 420 425 430 ctg cac cag gac tgg ctg aat ggc aag gag tac aagtgc aag gtc tcc 1344 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys CysLys Val Ser 435 440 445 aac aaa gcc ctc cca gcc ccc atc gag aaa acc atctcc aaa gcc aaa 1392 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile SerLys Ala Lys 450 455 460 ggg cag ccc cga gaa cca cag gtg tac acc ctg ccccca tcc cgg gat 1440 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro ProSer Arg Asp 465 470 475 480 gag ctg acc aag aac cag gtc agc ctg acc tgcctg gtc aaa ggc ttc 1488 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys LeuVal Lys Gly Phe 485 490 495 tat ccc agc gac atc gcc gtg gag tgg gag agcaat ggg cag ccg gag 1536 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser AsnGly Gln Pro Glu 500 505 510 aac aac tac aag acc acg cct ccc gtg ctg gactcc gac ggc tcc ttc 1584 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp SerAsp Gly Ser Phe 515 520 525 ttc ctc tac agc aag ctc acc gtg gac aag agcagg tgg cag cag ggg 1632 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser ArgTrp Gln Gln Gly 530 535 540 aac gtc ttc tca tgc tcc gtg atg cat gag gctctg cac aac cac tac 1680 Asn Val Phe Ser Cys Ser Val Met His Glu Ala LeuHis Asn His Tyr 545 550 555 560 acg cag aag agc ctc tcc ctg tct ccg ggtaaa tgacgcg 1720 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 565 570 53571 PRT Homo sapiens 53 Met Arg Ala Pro Gly Arg Pro Ala Leu Arg Pro LeuLeu Leu Leu Leu 1 5 10 15 Leu Ala Ala Pro Trp Gly Arg Ala Val Pro CysVal Ser Gly Gly Leu 20 25 30 Pro Lys Pro Ala Asn Ile Thr Phe Leu Ser IleAsn Met Lys Asn Val 35 40 45 Leu Gln Trp Thr Pro Pro Glu Gly Leu Gln GlyVal Lys Val Thr Tyr 50 55 60 Thr Val Gln Tyr Phe Ile Tyr Gly Gln Lys LysTrp Leu Asn Lys Ser 65 70 75 80 Glu Cys Arg Asn Ile Asn Arg Thr Tyr CysAsp Leu Ser Ala Glu Thr 85 90 95 Ser Asp Tyr Glu His Gln Tyr Tyr Ala LysVal Lys Ala Ile Trp Gly 100 105 110 Thr Lys Cys Ser Lys Trp Ala Glu SerGly Arg Phe Tyr Pro Phe Leu 115 120 125 Glu Thr Gln Ile Gly Pro Pro GluVal Ala Leu Thr Thr Asp Glu Lys 130 135 140 Ser Ile Ser Val Val Leu ThrAla Pro Glu Lys Trp Lys Arg Asn Pro 145 150 155 160 Glu Asp Leu Pro ValSer Met Gln Gln Ile Tyr Ser Asn Leu Lys Tyr 165 170 175 Asn Val Ser ValLeu Asn Thr Lys Ser Asn Arg Thr Trp Ser Gln Cys 180 185 190 Val Thr AsnHis Thr Leu Val Leu Thr Trp Leu Glu Pro Asn Thr Leu 195 200 205 Tyr CysVal His Val Glu Ser Phe Val Pro Gly Pro Pro Arg Arg Ala 210 215 220 GlnPro Ser Glu Lys Gln Cys Ala Arg Thr Leu Lys Asp Gln Ser Ser 225 230 235240 Glu Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 245250 255 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp260 265 270 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala LeuThr 275 280 285 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser GlyLeu Tyr 290 295 300 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser LeuGly Thr Gln 305 310 315 320 Thr Tyr Ile Cys Asn Val Asn His Lys Pro SerAsn Thr Lys Val Asp 325 330 335 Lys Lys Val Glu Pro Lys Ser Cys Asp LysThr His Thr Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Leu Leu Gly GlyPro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu MetIle Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val SerHis Glu Asp Pro Glu Val Lys Phe Asn 385 390 395 400 Trp Tyr Val Asp GlyVal Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln TyrAsn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His GlnAsp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn LysAla Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 GlyGln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 465 470 475480 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 485490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly SerPhe 515 520 525 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp GlnGln Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu HisAsn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys565 570 54 547 PRT Homo sapiens 54 Val Pro Cys Val Ser Gly Gly Leu ProLys Pro Ala Asn Ile Thr Phe 1 5 10 15 Leu Ser Ile Asn Met Lys Asn ValLeu Gln Trp Thr Pro Pro Glu Gly 20 25 30 Leu Gln Gly Val Lys Val Thr TyrThr Val Gln Tyr Phe Ile Tyr Gly 35 40 45 Gln Lys Lys Trp Leu Asn Lys SerGlu Cys Arg Asn Ile Asn Arg Thr 50 55 60 Tyr Cys Asp Leu Ser Ala Glu ThrSer Asp Tyr Glu His Gln Tyr Tyr 65 70 75 80 Ala Lys Val Lys Ala Ile TrpGly Thr Lys Cys Ser Lys Trp Ala Glu 85 90 95 Ser Gly Arg Phe Tyr Pro PheLeu Glu Thr Gln Ile Gly Pro Pro Glu 100 105 110 Val Ala Leu Thr Thr AspGlu Lys Ser Ile Ser Val Val Leu Thr Ala 115 120 125 Pro Glu Lys Trp LysArg Asn Pro Glu Asp Leu Pro Val Ser Met Gln 130 135 140 Gln Ile Tyr SerAsn Leu Lys Tyr Asn Val Ser Val Leu Asn Thr Lys 145 150 155 160 Ser AsnArg Thr Trp Ser Gln Cys Val Thr Asn His Thr Leu Val Leu 165 170 175 ThrTrp Leu Glu Pro Asn Thr Leu Tyr Cys Val His Val Glu Ser Phe 180 185 190Val Pro Gly Pro Pro Arg Arg Ala Gln Pro Ser Glu Lys Gln Cys Ala 195 200205 Arg Thr Leu Lys Asp Gln Ser Ser Glu Ala Ser Thr Lys Gly Pro Ser 210215 220 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala225 230 235 240 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro ValThr Val 245 250 255 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His ThrPhe Pro Ala 260 265 270 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser SerVal Val Thr Val 275 280 285 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr IleCys Asn Val Asn His 290 295 300 Lys Pro Ser Asn Thr Lys Val Asp Lys LysVal Glu Pro Lys Ser Cys 305 310 315 320 Asp Lys Thr His Thr Cys Pro ProCys Pro Ala Pro Glu Leu Leu Gly 325 330 335 Gly Pro Ser Val Phe Leu PhePro Pro Lys Pro Lys Asp Thr Leu Met 340 345 350 Ile Ser Arg Thr Pro GluVal Thr Cys Val Val Val Asp Val Ser His 355 360 365 Glu Asp Pro Glu ValLys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 370 375 380 His Asn Ala LysThr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 385 390 395 400 Arg ValVal Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 405 410 415 LysGlu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 420 425 430Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 435 440445 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 450455 460 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu465 470 475 480 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr ThrPro Pro 485 490 495 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser LysLeu Thr Val 500 505 510 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe SerCys Ser Val Met 515 520 525 His Glu Ala Leu His Asn His Tyr Thr Gln LysSer Leu Ser Leu Ser 530 535 540 Pro Gly Lys 545 55 217 PRT Homo sapiens55 Val Pro Cys Val Ser Gly Gly Leu Pro Lys Pro Ala Asn Ile Thr Phe 1 510 15 Leu Ser Ile Asn Met Lys Asn Val Leu Gln Trp Thr Pro Pro Glu Gly 2025 30 Leu Gln Gly Val Lys Val Thr Tyr Thr Val Gln Tyr Phe Ile Tyr Gly 3540 45 Gln Lys Lys Trp Leu Asn Lys Ser Glu Cys Arg Asn Ile Asn Arg Thr 5055 60 Tyr Cys Asp Leu Ser Ala Glu Thr Ser Asp Tyr Glu His Gln Tyr Tyr 6570 75 80 Ala Lys Val Lys Ala Ile Trp Gly Thr Lys Cys Ser Lys Trp Ala Glu85 90 95 Ser Gly Arg Phe Tyr Pro Phe Leu Glu Thr Gln Ile Gly Pro Pro Glu100 105 110 Val Ala Leu Thr Thr Asp Glu Lys Ser Ile Ser Val Val Leu ThrAla 115 120 125 Pro Glu Lys Trp Lys Arg Asn Pro Glu Asp Leu Pro Val SerMet Gln 130 135 140 Gln Ile Tyr Ser Asn Leu Lys Tyr Asn Val Ser Val LeuAsn Thr Lys 145 150 155 160 Ser Asn Arg Thr Trp Ser Gln Cys Val Thr AsnHis Thr Leu Val Leu 165 170 175 Thr Trp Leu Glu Pro Asn Thr Leu Tyr CysVal His Val Glu Ser Phe 180 185 190 Val Pro Gly Pro Pro Arg Arg Ala GlnPro Ser Glu Lys Gln Cys Ala 195 200 205 Arg Thr Leu Lys Asp Gln Ser SerGlu 210 215 56 1011 DNA Homo sapiens CDS (1)...(1008) 56 atg cag act ttcaca atg gtt cta gaa gaa atc tgg aca agt ctt ttc 48 Met Gln Thr Phe ThrMet Val Leu Glu Glu Ile Trp Thr Ser Leu Phe 1 5 10 15 atg tgg ttt ttctac gca ttg att cca tgt ttg ctc aca gat gaa gtg 96 Met Trp Phe Phe TyrAla Leu Ile Pro Cys Leu Leu Thr Asp Glu Val 20 25 30 gcc att ctg cct gcccct cag aac ctc tct gta ctc tca acc aac atg 144 Ala Ile Leu Pro Ala ProGln Asn Leu Ser Val Leu Ser Thr Asn Met 35 40 45 aag cat ctc ttg atg tggagc cca gtg atc gcg cct gga gaa aca gtg 192 Lys His Leu Leu Met Trp SerPro Val Ile Ala Pro Gly Glu Thr Val 50 55 60 tac tat tct gtc gaa tac cagggg gag tac gag agc ctg tac acg agc 240 Tyr Tyr Ser Val Glu Tyr Gln GlyGlu Tyr Glu Ser Leu Tyr Thr Ser 65 70 75 80 cac atc tgg atc ccc agc agctgg tgc tca ctc act gaa ggt cct gag 288 His Ile Trp Ile Pro Ser Ser TrpCys Ser Leu Thr Glu Gly Pro Glu 85 90 95 tgt gat gtc act gat gac atc acggcc act gtg cca tac aac ctt cgt 336 Cys Asp Val Thr Asp Asp Ile Thr AlaThr Val Pro Tyr Asn Leu Arg 100 105 110 gtc agg gcc aca ttg ggc tca cagacc tca gcc tgg agc atc ctg aag 384 Val Arg Ala Thr Leu Gly Ser Gln ThrSer Ala Trp Ser Ile Leu Lys 115 120 125 cat ccc ttt aat aga aac tca accatc ctt acc cga cct ggg atg gag 432 His Pro Phe Asn Arg Asn Ser Thr IleLeu Thr Arg Pro Gly Met Glu 130 135 140 atc acc aaa gat ggc ttc cac ctggtt att gag ctg gag gac ctg ggg 480 Ile Thr Lys Asp Gly Phe His Leu ValIle Glu Leu Glu Asp Leu Gly 145 150 155 160 ccc cag ttt gag ttc ctt gtggcc tac tgg agg agg gag cct ggt gcc 528 Pro Gln Phe Glu Phe Leu Val AlaTyr Trp Arg Arg Glu Pro Gly Ala 165 170 175 gag gaa cat gtc aaa atg gtgagg agt ggg ggt att cca gtg cac cta 576 Glu Glu His Val Lys Met Val ArgSer Gly Gly Ile Pro Val His Leu 180 185 190 gaa acc atg gag cca ggg gctgca tac tgt gtg aag gcc cag aca ttc 624 Glu Thr Met Glu Pro Gly Ala AlaTyr Cys Val Lys Ala Gln Thr Phe 195 200 205 gtg aag gcc att ggg agg tacagc gcc ttc agc cag aca gaa tgt gtg 672 Val Lys Ala Ile Gly Arg Tyr SerAla Phe Ser Gln Thr Glu Cys Val 210 215 220 gag gtg caa gga gag gcc actgtg gct gca cca tct gtc ttc atc ttc 720 Glu Val Gln Gly Glu Ala Thr ValAla Ala Pro Ser Val Phe Ile Phe 225 230 235 240 ccg cca tct gat gag cagttg aaa tct ggt acc gcc tct gtt gtg tgc 768 Pro Pro Ser Asp Glu Gln LeuLys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 ctg ctg aat aac ttc tatccc aga gag gcc aaa gta cag tgg aag gtg 816 Leu Leu Asn Asn Phe Tyr ProArg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 gat aac gcc ctc caa tcgggt aac tcc cag gag agt gtc aca gag cag 864 Asp Asn Ala Leu Gln Ser GlyAsn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 gac agc aag gac agc acctac agc ctc agc agc acc ctg acg ctg agc 912 Asp Ser Lys Asp Ser Thr TyrSer Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 aaa gca gac tac gag aaacac aaa gtc tac gcc tgc gaa gtc acc cat 960 Lys Ala Asp Tyr Glu Lys HisLys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 cag ggc ctg agc tcgccc gtc aca aag agc ttc aac agg gga gag tgt 1008 Gln Gly Leu Ser Ser ProVal Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 tag 1011 57 336 PRTHomo sapiens 57 Met Gln Thr Phe Thr Met Val Leu Glu Glu Ile Trp Thr SerLeu Phe 1 5 10 15 Met Trp Phe Phe Tyr Ala Leu Ile Pro Cys Leu Leu ThrAsp Glu Val 20 25 30 Ala Ile Leu Pro Ala Pro Gln Asn Leu Ser Val Leu SerThr Asn Met 35 40 45 Lys His Leu Leu Met Trp Ser Pro Val Ile Ala Pro GlyGlu Thr Val 50 55 60 Tyr Tyr Ser Val Glu Tyr Gln Gly Glu Tyr Glu Ser LeuTyr Thr Ser 65 70 75 80 His Ile Trp Ile Pro Ser Ser Trp Cys Ser Leu ThrGlu Gly Pro Glu 85 90 95 Cys Asp Val Thr Asp Asp Ile Thr Ala Thr Val ProTyr Asn Leu Arg 100 105 110 Val Arg Ala Thr Leu Gly Ser Gln Thr Ser AlaTrp Ser Ile Leu Lys 115 120 125 His Pro Phe Asn Arg Asn Ser Thr Ile LeuThr Arg Pro Gly Met Glu 130 135 140 Ile Thr Lys Asp Gly Phe His Leu ValIle Glu Leu Glu Asp Leu Gly 145 150 155 160 Pro Gln Phe Glu Phe Leu ValAla Tyr Trp Arg Arg Glu Pro Gly Ala 165 170 175 Glu Glu His Val Lys MetVal Arg Ser Gly Gly Ile Pro Val His Leu 180 185 190 Glu Thr Met Glu ProGly Ala Ala Tyr Cys Val Lys Ala Gln Thr Phe 195 200 205 Val Lys Ala IleGly Arg Tyr Ser Ala Phe Ser Gln Thr Glu Cys Val 210 215 220 Glu Val GlnGly Glu Ala Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 ProPro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val ThrHis 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn ArgGly Glu Cys 325 330 335 58 307 PRT Homo sapiens 58 Asp Glu Val Ala IleLeu Pro Ala Pro Gln Asn Leu Ser Val Leu Ser 1 5 10 15 Thr Asn Met LysHis Leu Leu Met Trp Ser Pro Val Ile Ala Pro Gly 20 25 30 Glu Thr Val TyrTyr Ser Val Glu Tyr Gln Gly Glu Tyr Glu Ser Leu 35 40 45 Tyr Thr Ser HisIle Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu 50 55 60 Gly Pro Glu CysAsp Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr 65 70 75 80 Asn Leu ArgVal Arg Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser 85 90 95 Ile Leu LysHis Pro Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro 100 105 110 Gly MetGlu Ile Thr Lys Asp Gly Phe His Leu Val Ile Glu Leu Glu 115 120 125 AspLeu Gly Pro Gln Phe Glu Phe Leu Val Ala Tyr Trp Arg Arg Glu 130 135 140Pro Gly Ala Glu Glu His Val Lys Met Val Arg Ser Gly Gly Ile Pro 145 150155 160 Val His Leu Glu Thr Met Glu Pro Gly Ala Ala Tyr Cys Val Lys Ala165 170 175 Gln Thr Phe Val Lys Ala Ile Gly Arg Tyr Ser Ala Phe Ser GlnThr 180 185 190 Glu Cys Val Glu Val Gln Gly Glu Ala Thr Val Ala Ala ProSer Val 195 200 205 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser GlyThr Ala Ser 210 215 220 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg GluAla Lys Val Gln 225 230 235 240 Trp Lys Val Asp Asn Ala Leu Gln Ser GlyAsn Ser Gln Glu Ser Val 245 250 255 Thr Glu Gln Asp Ser Lys Asp Ser ThrTyr Ser Leu Ser Ser Thr Leu 260 265 270 Thr Leu Ser Lys Ala Asp Tyr GluLys His Lys Val Tyr Ala Cys Glu 275 280 285 Val Thr His Gln Gly Leu SerSer Pro Val Thr Lys Ser Phe Asn Arg 290 295 300 Gly Glu Cys 305 59 201PRT Homo sapiens 59 Asp Glu Val Ala Ile Leu Pro Ala Pro Gln Asn Leu SerVal Leu Ser 1 5 10 15 Thr Asn Met Lys His Leu Leu Met Trp Ser Pro ValIle Ala Pro Gly 20 25 30 Glu Thr Val Tyr Tyr Ser Val Glu Tyr Gln Gly GluTyr Glu Ser Leu 35 40 45 Tyr Thr Ser His Ile Trp Ile Pro Ser Ser Trp CysSer Leu Thr Glu 50 55 60 Gly Pro Glu Cys Asp Val Thr Asp Asp Ile Thr AlaThr Val Pro Tyr 65 70 75 80 Asn Leu Arg Val Arg Ala Thr Leu Gly Ser GlnThr Ser Ala Trp Ser 85 90 95 Ile Leu Lys His Pro Phe Asn Arg Asn Ser ThrIle Leu Thr Arg Pro 100 105 110 Gly Met Glu Ile Thr Lys Asp Gly Phe HisLeu Val Ile Glu Leu Glu 115 120 125 Asp Leu Gly Pro Gln Phe Glu Phe LeuVal Ala Tyr Trp Arg Arg Glu 130 135 140 Pro Gly Ala Glu Glu His Val LysMet Val Arg Ser Gly Gly Ile Pro 145 150 155 160 Val His Leu Glu Thr MetGlu Pro Gly Ala Ala Tyr Cys Val Lys Ala 165 170 175 Gln Thr Phe Val LysAla Ile Gly Arg Tyr Ser Ala Phe Ser Gln Thr 180 185 190 Glu Cys Val GluVal Gln Gly Glu Ala 195 200 60 323 PRT Homo sapiens 60 Asp Glu Val AlaIle Leu Pro Ala Pro Gln Asn Leu Ser Val Leu Ser 1 5 10 15 Thr Asn MetLys His Leu Leu Met Trp Ser Pro Val Ile Ala Pro Gly 20 25 30 Glu Thr ValTyr Tyr Ser Val Glu Tyr Gln Gly Glu Tyr Glu Ser Leu 35 40 45 Tyr Thr SerHis Ile Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu 50 55 60 Gly Pro GluCys Asp Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr 65 70 75 80 Asn LeuArg Val Arg Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser 85 90 95 Ile LeuLys His Pro Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro 100 105 110 GlyMet Glu Ile Pro Lys His Gly Phe His Leu Val Ile Glu Leu Glu 115 120 125Asp Leu Gly Pro Gln Phe Glu Phe Leu Val Ala Tyr Trp Thr Arg Glu 130 135140 Pro Gly Ala Glu Glu His Val Lys Met Val Arg Ser Gly Gly Ile Pro 145150 155 160 Val His Leu Glu Thr Met Glu Pro Gly Ala Ala Tyr Cys Val LysAla 165 170 175 Gln Thr Phe Val Lys Ala Ile Gly Arg Tyr Ser Ala Phe SerGln Thr 180 185 190 Glu Cys Val Glu Val Gln Gly Glu Ala Gly Gly Gly GlySer Gly Gly 195 200 205 Gly Gly Ser Gly Gly Gly Gly Ser Arg Thr Val AlaAla Pro Ser Val 210 215 220 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu LysSer Gly Thr Ala Ser 225 230 235 240 Val Val Cys Leu Leu Asn Asn Phe TyrPro Arg Glu Ala Lys Val Gln 245 250 255 Trp Lys Val Asp Asn Ala Leu GlnSer Gly Asn Ser Gln Glu Ser Val 260 265 270 Thr Glu Gln Asp Ser Lys AspSer Thr Tyr Ser Leu Ser Ser Thr Leu 275 280 285 Thr Leu Ser Lys Ala AspTyr Glu Lys His Lys Val Tyr Ala Cys Glu 290 295 300 Val Thr His Gln GlyLeu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 305 310 315 320 Gly Glu Cys61 201 PRT Homo sapiens 61 Asp Glu Val Ala Ile Leu Pro Ala Pro Gln AsnLeu Ser Val Leu Ser 1 5 10 15 Thr Asn Met Lys His Leu Leu Met Trp SerPro Val Ile Ala Pro Gly 20 25 30 Glu Thr Val Tyr Tyr Ser Val Glu Tyr GlnGly Glu Tyr Glu Ser Leu 35 40 45 Tyr Thr Ser His Ile Trp Ile Pro Ser SerTrp Cys Ser Leu Thr Glu 50 55 60 Gly Pro Glu Cys Asp Val Thr Asp Asp IleThr Ala Thr Val Pro Tyr 65 70 75 80 Asn Leu Arg Val Arg Ala Thr Leu GlySer Gln Thr Ser Ala Trp Ser 85 90 95 Ile Leu Lys His Pro Phe Asn Arg AsnSer Thr Ile Leu Thr Arg Pro 100 105 110 Gly Met Glu Ile Pro Lys His GlyPhe His Leu Val Ile Glu Leu Glu 115 120 125 Asp Leu Gly Pro Gln Phe GluPhe Leu Val Ala Tyr Trp Thr Arg Glu 130 135 140 Pro Gly Ala Glu Glu HisVal Lys Met Val Arg Ser Gly Gly Ile Pro 145 150 155 160 Val His Leu GluThr Met Glu Pro Gly Ala Ala Tyr Cys Val Lys Ala 165 170 175 Gln Thr PheVal Lys Ala Ile Gly Arg Tyr Ser Ala Phe Ser Gln Thr 180 185 190 Glu CysVal Glu Val Gln Gly Glu Ala 195 200 62 559 PRT Homo sapiens 62 Val ProCys Val Ser Gly Gly Leu Pro Lys Pro Ala Asn Ile Thr Phe 1 5 10 15 LeuSer Ile Asn Met Lys Asn Val Leu Gln Trp Thr Pro Pro Glu Gly 20 25 30 LeuGln Gly Val Lys Val Thr Tyr Thr Val Gln Tyr Phe Ile Tyr Gly 35 40 45 GlnLys Lys Trp Leu Asn Lys Ser Glu Cys Arg Asn Ile Asn Arg Thr 50 55 60 TyrCys Asp Leu Ser Ala Glu Thr Ser Asp Tyr Glu His Gln Tyr Tyr 65 70 75 80Ala Lys Val Lys Ala Ile Trp Gly Thr Lys Cys Ser Lys Trp Ala Glu 85 90 95Ser Gly Arg Phe Tyr Pro Phe Leu Glu Thr Gln Ile Gly Pro Pro Glu 100 105110 Val Ala Leu Thr Thr Asp Glu Lys Ser Ile Ser Val Val Leu Thr Ala 115120 125 Pro Glu Lys Trp Lys Arg Asn Pro Glu Asp Leu Pro Val Ser Met Gln130 135 140 Gln Ile Tyr Ser Asn Leu Lys Tyr Asn Val Ser Val Leu Asn ThrLys 145 150 155 160 Ser Asn Arg Thr Trp Ser Gln Cys Val Thr Asn His ThrLeu Val Leu 165 170 175 Thr Trp Leu Glu Pro Asn Thr Leu Tyr Cys Val HisVal Glu Ser Phe 180 185 190 Val Pro Gly Pro Pro Arg Arg Ala Gln Pro SerGlu Lys Gln Cys Ala 195 200 205 Arg Thr Leu Lys Asp Gln Gly Gly Gly GlySer Gly Gly Gly Gly Ser 210 215 220 Gly Gly Gly Gly Ser Ala Ser Thr LysGly Pro Ser Val Phe Pro Leu 225 230 235 240 Ala Pro Ser Ser Lys Ser ThrSer Gly Gly Thr Ala Ala Leu Gly Cys 245 250 255 Leu Val Lys Asp Tyr PhePro Glu Pro Val Thr Val Ser Trp Asn Ser 260 265 270 Gly Ala Leu Thr SerGly Val His Thr Phe Pro Ala Val Leu Gln Ser 275 280 285 Ser Gly Leu TyrSer Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 290 295 300 Leu Gly ThrGln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 305 310 315 320 ThrLys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 325 330 335Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val 340 345350 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 355360 365 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu370 375 380 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn AlaLys 385 390 395 400 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr ArgVal Val Ser 405 410 415 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn GlyLys Glu Tyr Lys 420 425 430 Cys Lys Val Ser Asn Lys Ala Leu Pro Ser SerIle Glu Lys Thr Ile 435 440 445 Ser Lys Ala Lys Gly Gln Pro Arg Glu ProGln Val Tyr Thr Leu Pro 450 455 460 Pro Ser Arg Asp Glu Leu Thr Lys AsnGln Val Ser Leu Thr Cys Leu 465 470 475 480 Val Lys Gly Phe Tyr Pro SerAsp Ile Ala Val Glu Trp Glu Ser Asn 485 490 495 Gly Gln Pro Glu Asn AsnTyr Lys Thr Thr Pro Pro Val Leu Asp Ser 500 505 510 Asp Gly Ser Phe PheLeu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 515 520 525 Trp Gln Gln GlyAsn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 530 535 540 His Asn HisTyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 545 550 555 63 214 PRTHomo sapiens 63 Val Pro Cys Val Ser Gly Gly Leu Pro Lys Pro Ala Asn IleThr Phe 1 5 10 15 Leu Ser Ile Asn Met Lys Asn Val Leu Gln Trp Thr ProPro Glu Gly 20 25 30 Leu Gln Gly Val Lys Val Thr Tyr Thr Val Gln Tyr PheIle Tyr Gly 35 40 45 Gln Lys Lys Trp Leu Asn Lys Ser Glu Cys Arg Asn IleAsn Arg Thr 50 55 60 Tyr Cys Asp Leu Ser Ala Glu Thr Ser Asp Tyr Glu HisGln Tyr Tyr 65 70 75 80 Ala Lys Val Lys Ala Ile Trp Gly Thr Lys Cys SerLys Trp Ala Glu 85 90 95 Ser Gly Arg Phe Tyr Pro Phe Leu Glu Thr Gln IleGly Pro Pro Glu 100 105 110 Val Ala Leu Thr Thr Asp Glu Lys Ser Ile SerVal Val Leu Thr Ala 115 120 125 Pro Glu Lys Trp Lys Arg Asn Pro Glu AspLeu Pro Val Ser Met Gln 130 135 140 Gln Ile Tyr Ser Asn Leu Lys Tyr AsnVal Ser Val Leu Asn Thr Lys 145 150 155 160 Ser Asn Arg Thr Trp Ser GlnCys Val Thr Asn His Thr Leu Val Leu 165 170 175 Thr Trp Leu Glu Pro AsnThr Leu Tyr Cys Val His Val Glu Ser Phe 180 185 190 Val Pro Gly Pro ProArg Arg Ala Gln Pro Ser Glu Lys Gln Cys Ala 195 200 205 Arg Thr Leu LysAsp Gln 210 64 19 PRT Homo sapiens 64 Glu Glu Ile His Ala Glu Leu ArgArg Phe Arg Arg Val Pro Cys Val 1 5 10 15 Ser Gly Gly 65 207 PRT Homosapiens 65 Leu Pro Lys Pro Ala Asn Ile Thr Phe Leu Ser Ile Asn Met LysAsn 1 5 10 15 Val Leu Gln Trp Thr Pro Pro Glu Gly Leu Gln Gly Val LysVal Thr 20 25 30 Tyr Thr Val Gln Tyr Phe Ile Tyr Gly Gln Lys Lys Trp LeuAsn Lys 35 40 45 Ser Glu Cys Arg Asn Ile Asn Arg Thr Tyr Cys Asp Leu SerAla Glu 50 55 60 Thr Ser Asp Tyr Glu His Gln Tyr Tyr Ala Lys Val Lys AlaIle Trp 65 70 75 80 Gly Thr Lys Cys Ser Lys Trp Ala Glu Ser Gly Arg PheTyr Pro Phe 85 90 95 Leu Glu Thr Gln Ile Gly Pro Pro Glu Val Ala Leu ThrThr Asp Glu 100 105 110 Lys Ser Ile Ser Val Val Leu Thr Ala Pro Glu LysTrp Lys Arg Asn 115 120 125 Pro Glu Asp Leu Pro Val Ser Met Gln Gln IleTyr Ser Asn Leu Lys 130 135 140 Tyr Asn Val Ser Val Leu Asn Thr Lys SerAsn Arg Thr Trp Ser Gln 145 150 155 160 Cys Val Thr Asn His Thr Leu ValLeu Thr Trp Leu Glu Pro Asn Thr 165 170 175 Leu Tyr Cys Val His Val GluSer Phe Val Pro Gly Pro Pro Arg Arg 180 185 190 Ala Gln Pro Ser Glu LysGln Cys Ala Arg Thr Leu Lys Asp Gln 195 200 205 66 150 PRT Homo sapiens66 Cys Arg Asn Ile Asn Arg Thr Tyr Cys Asp Leu Ser Ala Glu Thr Ser 1 510 15 Asp Tyr Glu His Gln Tyr Tyr Ala Lys Val Lys Ala Ile Trp Gly Thr 2025 30 Lys Cys Ser Lys Trp Ala Glu Ser Gly Arg Phe Tyr Pro Phe Leu Glu 3540 45 Thr Gln Ile Gly Pro Pro Glu Val Ala Leu Thr Thr Asp Glu Lys Ser 5055 60 Ile Ser Val Val Leu Thr Ala Pro Glu Lys Trp Lys Arg Asn Pro Glu 6570 75 80 Asp Leu Pro Val Ser Met Gln Gln Ile Tyr Ser Asn Leu Lys Tyr Asn85 90 95 Val Ser Val Leu Asn Thr Lys Ser Asn Arg Thr Trp Ser Gln Cys Val100 105 110 Thr Asn His Thr Leu Val Leu Thr Trp Leu Glu Pro Asn Thr LeuTyr 115 120 125 Cys Val His Val Glu Ser Phe Val Pro Gly Pro Pro Arg ArgAla Gln 130 135 140 Pro Ser Glu Lys Gln Cys 145 150 67 196 PRT Homosapiens 67 Leu Pro Ala Pro Gln Asn Leu Ser Val Leu Ser Thr Asn Met LysHis 1 5 10 15 Leu Leu Met Trp Ser Pro Val Ile Ala Pro Gly Glu Thr ValTyr Tyr 20 25 30 Ser Val Glu Tyr Gln Gly Glu Tyr Glu Ser Leu Tyr Thr SerHis Ile 35 40 45 Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu Gly Pro GluCys Asp 50 55 60 Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr Asn Leu ArgVal Arg 65 70 75 80 Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser Ile LeuLys His Pro 85 90 95 Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro Gly MetGlu Ile Thr 100 105 110 Lys Asp Gly Phe His Leu Val Ile Glu Leu Glu AspLeu Gly Pro Gln 115 120 125 Phe Glu Phe Leu Val Ala Tyr Trp Arg Arg GluPro Gly Ala Glu Glu 130 135 140 His Val Lys Met Val Arg Ser Gly Gly IlePro Val His Leu Glu Thr 145 150 155 160 Met Glu Pro Gly Ala Ala Tyr CysVal Lys Ala Gln Thr Phe Val Lys 165 170 175 Ala Ile Gly Arg Tyr Ser AlaPhe Ser Gln Thr Glu Cys Val Glu Val 180 185 190 Gln Gly Glu Ala 195 68203 PRT Homo sapiens 68 Asp Glu Val Ala Ile Leu Pro Ala Pro Gln Asn LeuSer Val Leu Ser 1 5 10 15 Thr Asn Met Lys His Leu Leu Met Trp Ser ProVal Ile Ala Pro Gly 20 25 30 Glu Thr Val Tyr Tyr Ser Val Glu Tyr Gln GlyGlu Tyr Glu Ser Leu 35 40 45 Tyr Thr Ser His Ile Trp Ile Pro Ser Ser TrpCys Ser Leu Thr Glu 50 55 60 Gly Pro Glu Cys Asp Val Thr Asp Asp Ile ThrAla Thr Val Pro Tyr 65 70 75 80 Asn Leu Arg Val Arg Ala Thr Leu Gly SerGln Thr Ser Ala Trp Ser 85 90 95 Ile Leu Lys His Pro Phe Asn Arg Asn SerThr Ile Leu Thr Arg Pro 100 105 110 Gly Met Glu Ile Pro Lys His Gly PheHis Leu Val Ile Glu Leu Glu 115 120 125 Asp Leu Gly Pro Gln Phe Glu PheLeu Val Ala Tyr Trp Thr Arg Glu 130 135 140 Pro Gly Ala Glu Glu His ValLys Met Val Arg Ser Gly Gly Ile Pro 145 150 155 160 Val His Leu Glu ThrMet Glu Pro Gly Ala Ala Tyr Cys Val Lys Ala 165 170 175 Gln Thr Phe ValLys Ala Ile Gly Arg Tyr Ser Ala Phe Ser Gln Thr 180 185 190 Glu Cys ValGlu Val Gln Gly Glu Ala Ile Pro 195 200 69 196 PRT Homo sapiens 69 LeuPro Ala Pro Gln Asn Leu Ser Val Leu Ser Thr Asn Met Lys His 1 5 10 15Leu Leu Met Trp Ser Pro Val Ile Ala Pro Gly Glu Thr Val Tyr Tyr 20 25 30Ser Val Glu Tyr Gln Gly Glu Tyr Glu Ser Leu Tyr Thr Ser His Ile 35 40 45Trp Ile Pro Ser Ser Trp Cys Ser Leu Thr Glu Gly Pro Glu Cys Asp 50 55 60Val Thr Asp Asp Ile Thr Ala Thr Val Pro Tyr Asn Leu Arg Val Arg 65 70 7580 Ala Thr Leu Gly Ser Gln Thr Ser Ala Trp Ser Ile Leu Lys His Pro 85 9095 Phe Asn Arg Asn Ser Thr Ile Leu Thr Arg Pro Gly Met Glu Ile Pro 100105 110 Lys His Gly Phe His Leu Val Ile Glu Leu Glu Asp Leu Gly Pro Gln115 120 125 Phe Glu Phe Leu Val Ala Tyr Trp Thr Arg Glu Pro Gly Ala GluGlu 130 135 140 His Val Lys Met Val Arg Ser Gly Gly Ile Pro Val His LeuGlu Thr 145 150 155 160 Met Glu Pro Gly Ala Ala Tyr Cys Val Lys Ala GlnThr Phe Val Lys 165 170 175 Ala Ile Gly Arg Tyr Ser Ala Phe Ser Gln ThrGlu Cys Val Glu Val 180 185 190 Gln Gly Glu Ala 195 70 135 PRT Homosapiens 70 Cys Ser Leu Thr Glu Gly Pro Glu Cys Asp Val Thr Asp Asp IleThr 1 5 10 15 Ala Thr Val Pro Tyr Asn Leu Arg Val Arg Ala Thr Leu GlySer Gln 20 25 30 Thr Ser Ala Trp Ser Ile Leu Lys His Pro Phe Asn Arg AsnSer Thr 35 40 45 Ile Leu Thr Arg Pro Gly Met Glu Ile Thr Lys Asp Gly PheHis Leu 50 55 60 Val Ile Glu Leu Glu Asp Leu Gly Pro Gln Phe Glu Phe LeuVal Ala 65 70 75 80 Tyr Trp Arg Arg Glu Pro Gly Ala Glu Glu His Val LysMet Val Arg 85 90 95 Ser Gly Gly Ile Pro Val His Leu Glu Thr Met Glu ProGly Ala Ala 100 105 110 Tyr Cys Val Lys Ala Gln Thr Phe Val Lys Ala IleGly Arg Tyr Ser 115 120 125 Ala Phe Ser Gln Thr Glu Cys 130 135 71 135PRT Homo sapiens 71 Cys Ser Leu Thr Glu Gly Pro Glu Cys Asp Val Thr AspAsp Ile Thr 1 5 10 15 Ala Thr Val Pro Tyr Asn Leu Arg Val Arg Ala ThrLeu Gly Ser Gln 20 25 30 Thr Ser Ala Trp Ser Ile Leu Lys His Pro Phe AsnArg Asn Ser Thr 35 40 45 Ile Leu Thr Arg Pro Gly Met Glu Ile Pro Lys HisGly Phe His Leu 50 55 60 Val Ile Glu Leu Glu Asp Leu Gly Pro Gln Phe GluPhe Leu Val Ala 65 70 75 80 Tyr Trp Thr Arg Glu Pro Gly Ala Glu Glu HisVal Lys Met Val Arg 85 90 95 Ser Gly Gly Ile Pro Val His Leu Glu Thr MetGlu Pro Gly Ala Ala 100 105 110 Tyr Cys Val Lys Ala Gln Thr Phe Val LysAla Ile Gly Arg Tyr Ser 115 120 125 Ala Phe Ser Gln Thr Glu Cys 130 13572 15 PRT Homo sapiens 72 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser GlyGly Gly Gly Ser 1 5 10 15

What is claimed is:
 1. A method for treating a mammal afflicted with adisease in which an IL-20 polypeptide plays a role, wherein the IL-20polypeptide is comprised of an amino acid sequence selected from thegroup consisting of SEQ ID Nos.: 1, 2, 3, 4, 5, 6, 7, 8 and 9,comprising: administering antagonist of said IL-20 polypeptide to saidindividual.
 2. The method of claim 1 wherein the antagonist is selectedfrom the group consisting of an antibody, antibody fragment or singlechain antibody that binds to said IL-20 polypeptide, a soluble receptorthat binds to said IL-20 polypeptide and an antibody, antibody fragmentor single chain antibody which binds to the soluble receptor of IL-20wherein said soluble receptor is comprised of an IL-20RA subunit and anIL-20RB subunit.
 3. The method of claim 2 wherein the soluble receptoris a comprised of the extracellular domain of IL-20RA and theextracellular domain of IL-20RB.
 4. The method of claim 3 wherein theextracellular domain of IL-20RA is fused to a constant region heavychain of an immunoglobulin (Ig) molecule, and the extracellular domainof IL-20RB is fused to a constant region of a light chain of an Igmolecule.
 5. The method of claim 2 wherein the antibody, antibodyfragment or single chain antibody, which binds to the IL-20 receptor,binds to the IL-20RA subunit.
 6. The method of claim 2 wherein theantibody, antibody fragment or single chain antibody, which binds to theIL-20 receptor, binds to the IL-20RB subunit.
 7. The method of claim 1wherein the disease that the IL-20 polypeptide plays a role is a skindisease selected from the group consisting of psoriasis, eczema, atopicdermatitis and contact dermatitis.
 8. The method of claim 1 wherein thedisease that the IL-20 polypeptide plays a role is an inflammatory lungselected from the group consisting of adult respiratory disease, asthma,bronchitis and pneumonia.
 9. A method for promoting the expression ofIL-8 in a cell comprising bringing the cell into contact with IL-20. 10.A method for increasing the expression of IL-8 in an individualcomprising administering IL-20 to said individual.